CN1152869A - 动脉粥样硬化和其它心血管疾病及炎症的治疗方法 - Google Patents
动脉粥样硬化和其它心血管疾病及炎症的治疗方法 Download PDFInfo
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- CN1152869A CN1152869A CN95194077A CN95194077A CN1152869A CN 1152869 A CN1152869 A CN 1152869A CN 95194077 A CN95194077 A CN 95194077A CN 95194077 A CN95194077 A CN 95194077A CN 1152869 A CN1152869 A CN 1152869A
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Abstract
二硫代羧化物类化合物,包括二硫代氨基甲酸盐,可阻断内皮细胞表面粘附分子VCAM-1的诱导表达,因此可用于治疗包括动脉粥样硬化在内的心血管疾病,也可以治疗由VCAM-1介导的非心血管性炎症。
Description
发明背景
本申请是关于动脉粥样硬化及其它心血管疾病和炎症的治疗方法和组合物。
白细胞与内皮的粘附是许多炎症早期的基本事件,这些炎症包括动脉粥样硬化,自身免疫疾病,细胞和病毒感染等。当内皮细胞表面可诱导的粘附分子受体与免疫细胞表面相应配体作用时,白细胞就开始向内皮募集。血管内皮细胞决定哪种白细胞可以募集(如单核细胞,淋巴细胞或中性白细胞),这是通过选择性表达特异的粘附分子,如血管细胞粘附分子-1(VCAM-1),胞内粘附分子-1(ICAM-1)和E-选择素。在动脉粥样硬化的最早阶段,VCAM-1在内皮上产生定位表达,选择性地募集表达有整合素对应受体VLA-4的单核白细胞。因为VLA-4选择性地表达于单核细胞和淋巴细胞,但在中性白细胞不表达。因此VCAM-1对介导单核白细胞的选择性粘附很重要。接下来白细胞转变为泡沫样(foamy)巨噬细胞,导致合成许多炎症细胞因子,生长因子和趋化因子,趋化因子有助于扩大白细胞和血小板募集,平滑肌细胞增殖,内皮细胞激活,和细胞外基质合成,这是正在成熟的动脉粥样硬化灶特点。
有过这样的假设,由反应性氧物质类(reactive oxygen species)将低密度脂蛋白(LDL)修饰为氧化型LDL(ox-LDL)是动脉粥样硬化起始和发展的中心事件。Steinber,et al.,N.Engl.J.Med.1989;320:915-924。氧化型LDL结构复杂,至少包括几个化学上各不相同的被氧化物质,每一物质,单独或结合起来,可以调节细胞因子-激活的粘附分子的基因表达。脂肪酸氢过氧化物如亚油基(linoleyl)氢过氧化物(13-HPODE)就是自由脂肪酸被脂氧化酶氧化产生的,是氧化LDL的重要成分。
当培养的人血管内皮细胞被脂多糖(LPS)和细胞因子,如白介素-1(IL-1),肿瘤坏死因子(TNF-α)激活后,可以表达VCAM-1。这些因子对细胞粘附分子表达的激活并不是选择性的。图1阐明了细胞因子激活血管内皮细胞中VCAM-1基因表达的过程。
血管内皮细胞中,细胞因子通过氧化还原敏感性调节因子如NF-κB对血管细胞粘附分子-1(VCAM-1)基因表达进行调节的图示(IκB是抑制性亚单位; NF-κB是核因子κB;NH3指蛋白的氨基末端,RNA PolII是RNA聚合酶II)。
通过对人VCAM-1基因上控制基因表达的调节元件进行分子分析,表明了转录调节因子核因子-κB(NF-κB)起重要作用,或对氧化还原敏感的VCAM-1基因表达的调节中;NF-κB类似的结合蛋白起重要作用。转录因子是-些蛋白分子,它们在核内通过与特定的DNA序列“增强子”结合,可以激活或抑制基因的表达,增强子-般位于基因启动子区附近,启动子是RNA合成起始的地方。核因子κB是-种广泛表达的多亚基转录因子,在几种细胞系中可以被大量不同的炎症介质如TNF-α, IL-1β,细菌内毒素和RNA病毒等激活。它在介导炎症及其它应激信号向核内调节器传导过程中起重要作用。尽管激活NF-κB的准确生化信号不清楚,但这个转录因子可以整入许多动脉粥样硬化危险因子和病原因子引起的共同分子通路中,如高血脂、吸烟、高血压和糖尿病。
重要的是,NF-κB在血管内皮细胞中被各种信号的激活可以被抗氧化剂如N-乙酰半胱氨酸和吡咯烷二硫代氨基甲酸盐特异性地抑制。(参见U.S.S.N.07/969,934,现已获许)这又引出下面的假设,氧离子基在NF-κB的激活中通过尚未阐明的氧化-还原机制发挥作用。又因为NF-κB类似的增强子元件也能以氧化-还原敏感方式调节VCAM-1启动子的转录,所以动脉粥状硬化损伤中,通过这种氧化-还原敏感的转录调节蛋白,氧化应激反应对VCAM-1基因表达的调节起重要作用。
有过这样的假设,由反应性氧物质类(reactive oxygen species)将低密度脂蛋白(LDL)修饰为氧化型LDL(ox-LDL)是动脉粥样硬化起始和发展的中心事件。Steinber,et al.,N.Engl.J.Med.1989;320:915-924。氧化型LDL结构复杂,至少包括几个化学上各不相同的被氧化物质,每一物质,单独或结合起来,可以调节细胞因子-激活的粘附分子的基因表达。脂肪酸氢过氧化物如亚油基(linoleyl)氢过氧化物(13-HPODE)就是自由脂肪酸被脂氧化酶氧化产生的,是氧化LDL的重要成分。
曾经认为,氧化脂是由细胞脂氧合酶系统作用形成的,氧化脂接下来就被传给LDL。此后,在转换金属和/或硫氢基化合物催化下基质中的LDL发生扩大反应。以前的观察证明,培养的内皮细胞中脂肪酸的修饰能改变细胞对氧化物伤害的敏感性。向培养的内皮细胞补充多饱和或单不饱和脂肪酸可降低细胞对氧化物伤害的敏感性,而补充多不饱和脂肪酸则增加细胞对氧化物伤害的敏感性。
用反向HPLC分析天然的和皂化的LDL脂提取物,表明13-HPODE是被激活的人单核细胞氧化的LDL中最主要的氧化脂肪酸。长期受氧化LDL的作用会对血管内皮细胞产生氧化信号,可能是通过某特殊的脂肪酸氢过氧化物,它选择性地增加细胞因子诱导的VCAM-1基因的表达。
通过某个还不清楚的机制,有动脉粥样硬化倾向的管壁区优先捕获循环的LDL。再通过一个不很清楚的通路,内皮,平滑肌和/或炎症细胞将LDL转变为氧化LDL。LDL的吸收是通过LDL受体,与此相反,单核细胞通过“清道夫”(scavenger)受体对氧化LDL进行迅速吸收,当LDL受体不同,“scavenger”受体的表达当胞内脂浓度上升时并不受抑制。因此,单核细胞持续吸收ox-LDL,成为脂吞性的泡沫状巨噬细胞,那些细胞形成脂肪斑纹(streak)
因为心血管疾病是当前美国社会主要的死亡原因,90%的心血管病又表现为动脉粥样硬化,因此急需有新的方法和药物对它进行治疗。对实现这个目标很重要的是发现并生产了特殊的氧化生物化合物,可用作炎症过程中间递质表达的选择性调节因子,特别是VCAM-1。更广泛的目标是找出选择性抑制氧化-还原敏感基因表达或激活被抑制的氧化-还原敏感基因的方法。
因此,为动脉粥样硬化及其它心血管病和炎症提供治疗方案是本发明的目的。
提供选择性抑制VCAM-1的方法是本发明的又一目的。
本发明的另一目的是提供由某氧化-还原敏感性基因表达或抑制所介导的人类疾病或紊乱的治疗方法。
本发明还有一个目的,就是为动脉粥样硬化,其它心血管疾病及炎症的治疗提供药用组合物。发明概述
已经发现多不饱和脂肪酸(“PUFAs”)和它们的氢过氧化物(“ox-PUFAs”)可以诱导人主动脉内皮细胞VCAM-1的表达,但不能诱导胞内粘附分子-1(ICAM-1)或E-选择素的表达。其中,“ox-PUFAs”是氧化修饰的低密度脂蛋白(LDL)中的重要成分。这种作用不是由细胞因子或其它非细胞因子介导的。这是对以前不清楚但很重要的VCAM-1介导免疫反应这一生物通路的实质性突破。
举一些非限制性的例子,亚油酸、亚麻酸、花生四烯酸、亚油基(linoley)氢过氧化物(13-HPODE)和花生四烯酸氢过氧化物(15-HPETE)诱导细胞表面分子VCAM-1的基因表达,但不诱导ICAM-1或E-选择素的表达。饱和脂肪酸(如硬脂酸)和单不饱和脂肪酸(如油酸)不能诱导VCAM-1,ICAM-1或E-选择素的表达。
PUFAs和它们的脂肪酸氢过氧化物对VCAM-1的诱导可以被抗氧化物吡咯烷二硫代氨基甲酸盐(PDTC)所抑制。这就表明这种诱导由氧化后的信号分子介导的,并且当信号分子的氧化被阻断(即氧化不发生),被逆转(即信号分子被还原),或当氧化-还原修饰的信号不能和调节的靶子相作用时,诱导也就不能发生了。
如果细胞长期暴露在多不饱和脂肪酸或它们相应的氧化物水平高于正常值的条件下,一种不正常的免疫反应就会启动,而且这与所呈现的威胁还不相当,它会导致病态。血管内皮细胞对PUFAs和ox-PUFAs的过分易感能加速诸如动脉粥样硬化灶等的形成。
基于这些发现,提出了动脉粥样硬化,血管成形术后再次狭窄,冠状动脉症,绞痛和其它心血管疾病,以及由VCAM-1介导的非心血管性炎症等的治疗方法,包括移去和降低氧化的多不饱和脂肪酸的浓度,或阻止它的形成,这些氧化多不饱和脂肪酸包括但不限于氧化亚油酸(C18Δ9,12),亚麻酸(C18Δ6,9,12),花生四烯酸(C20Δ5,8,11,14)和二十碳三烯酸(eicosatrienoic)(C20Δ8,11,14)。
由VCAM-1介导的非心血管性炎症的非限制性的例子包括类风湿病、骨关节炎、哮喘、皮炎和多发性硬化症。
这种方法在治疗心血管病时体现出很明显的优势,它超过了目前仅着眼于抑制病势发展的治疗措施,当使用得当时,通过阻止新的损伤发展和使已有损伤消退,从而可能治愈动脉粥样硬化。
在另一种实施方案中提供了抑制氧化-还原敏感基因或激活通过氧化-还原途径而被抑制的基因的方法,包括采用有效剂量的物质,阻止氧化信号的氧化,特别是多不饱和脂肪酸的氧化。包含于某免疫反应产生过程中有代表性的氧化-还原敏感基因包括那些表达细胞因子的基因,这些细胞因子包含于免疫反应起始过程中,如(IL-1β)促进炎症细胞向损伤部位迁移的趋化因子,(如MCP-1),生长因子(如,IL-6和凝血酶受体),和粘附分子(如VCAM-1和E-选择素)。
还提供了对由VCAM-1或氧化-还原敏感基因介导的疾病进行诊断的方法,包括病症替代标记的量化。在一个实施方案内,例如,对主体组织或血液中氧化的多不饱和脂肪酸或其它合适的标志物的量进行估计,用来估测主体“氧化状态”和主体对VCAM-1或氧化-还原敏感基因介导的疾病的敏感性。
在另一个实施方案中,循环中的或细胞表面的VCAM-1或其它合适的标记物水平,以及选用合适的抗氧化剂后对以上水平的效果,这些都可以进行量化。
然而在又一估测中,将主体血管内皮细胞对多不饱和脂肪酸或它们相应的氧化物的易感性进行估量。例如,可以通过下面的方式来完成这种估量,用PUFA或ox-PUFA刺激主体,将其细胞表面或循环中VCAM-1或其它替代标志物的浓度与正常群体进行比较。
在又一实施方案中,通过向主体动物使用过量PUFA或氧化的多不饱和脂肪酸而诱发疾病,建立了动脉粥样硬化或其它心脏或炎症的在体模型。这些动物模型可用于临床研究,使对这些疾病有进一步了解。
本发明的另一实施方案中,依据化合物治疗VCAM-1所介导的疾病的能力对其做出评估,而这种治疗能力又是根据它们对多不饱和脂肪酸的氧化或PUFA或ox-PUFA与靶蛋白相互作用的抑制效应。
这可以通过以下实验实现,用高水平PUFA或ox-PUFA刺激某主体,如人或动物如鼠,然后依据受测复合物降低循环中或细胞表面VCAM-1浓度的能力来确定化合物的疗效。与之不同,也可采用体外筛选,即在氧化物质如金属,例如铜,或酶诸如过氧化物酶,脂氧合酶,环氧合酶,或细胞色素P450等存在的条件下,根据受测复合物阻止PUFA氧化或PUFA或ox-PUFA与靶蛋白相互作用的能力筛选。
在另外的实施方案中,用TNF-α或其它VCAM-1诱导的物质对血管内皮细胞作用合适的时间,然后用任一种合适的方式如超声或冻融进行破碎。分离胞浆和胞膜部分。将放射性标记的PUFA加到定量的部分收集物中。在受测化合物存在或不存在的情况下,分别测定样品液体将PUFA转变成ox-PUFA的能力。也可以用完整的细胞代替细胞破碎体系。
吡咯烷二硫代氨基甲酸盐(PDTC)按每千克体重每天25-50mg的量口服,可以在食物诱导的兔超胆固醇症中极明显地抑制动脉粥样硬化脂肪斑的形成,动脉单核巨噬细胞炎症内皮VCAM-1的表达,其中血清胆固醇水平大于1000mg/dL,而这基本上是标准的内皮依赖性的舒张功能的结果。可是在同样的剂量下,其它推断为有疗效的药剂,如抗氧化剂普罗布考(probucol)和维生素E对此模型损伤的形成则无效果。
在动脉粥样硬化实验中,通过采用PDTC,可以使内皮依赖性的动脉舒张得到恢复。给饮食诱导的超胆固醇兔子模型口服PDTC(剂量为25-50mg/kg/day)使内皮依赖性的血管反应性恢复。这个结果由测试动物与对照动物切除下来的主动脉的环缩(ring-contraction)实验得到确定。在患有动脉粥样硬化的病人也证明了这一点,即通过非损害性Doppler流体实验检测,外周血管对充血条件的反应性规范。这是一种标准的,普遍可行,易于实行的检测,可以用来滴定有效药物水平的口服剂量。PDTC作为一种抗局部缺血的治疗措施,可以使内皮性来源的动脉扩张的病理损失迅速正常化,而上述症状是心血管疾病和动脉粥样硬化所共有的特征。这种血管血液流动的促进体现了症状和局部缺血限制的运动功能的促进,并提供了对血管保护的非损害性估测方法。内皮来源的血管舒张中其它不正常临床表现包括阳萎。
控制VCAM-1基因转录的分子调节器是一种新的转录因子复合物,包括NF-κB/Rel家族的P65和P50亚单位,与AP-1家族的c-fos和c-jun亚单位交联。通过结构和功能的研究表明,这些AP-1因子在VCAM-1启动子的调节中起重要的作用,而VCAM-1启动子是对VCAM-1基因表达进行治疗性调节的核心。这里首次证明了这个交联的转录复合物在内源基因的调节中的功能。
附图简述
图1是以下药物作用于人主动脉内皮细胞时,细胞表面VCAM-1的表达(O.D.450nm)对作用时间(小时)的函数,所用药物有细胞因子TNF-α(实心园圈);亚油酸(实心三角形);和亚油酸氢过氧化物(13-HPODE,实心正方形);以及没有药物作用(对照,空心正方形)。
图2是在亚油酸(实心三角)和亚油酸氢过氧化物(13-HPODE,实心方框)的作用下,人主动脉内皮细胞表面VCAM-1的表达(O.D.450nm)对脂肪酸浓度(μM)的函数。
图3是在细胞因子TNF-α,硬脂酸,油酸,亚油酸,亚麻酸和花生四烯酸的作用下,人主动脉内皮细胞表面VCAM-1,ICAM-1和E-选择素表达(O.D.450nm)的棒图。
图4是在有或没有抗氧化剂吡咯烷二硫代氨基甲酸盐的条件下,在亚油酸,13-HPODE,花生四烯酸,花生四烯酸氢过氧化物(15-HPETE)的作用下人主动脉内皮细胞表面VCAM-1表达的棒图(O.D.450nm)。
图5是一个放射自显影的图示,表明了亚油酸和13-HPODE对VCAM-1mRNA很明显的诱导。HAEC(人主动脉内皮细胞)受或不受亚油酸(7.5μM),13-HPODE(7.5μM)或TNF-α(100U/mL)等的作用。提取总RNA,取20μg用1.0%的琼脂糖-甲醛变性凝胶电泳进行大小片断分离,转移到硝酸纤维素膜,与32P-标记的人A)VCAM-1特异性或B)β-肌动蛋白特异性cDNA杂交。漂洗后,膜在-70℃下与X光片进行24小时的曝光,并使用增感屏。泳道确定:1)对照;2)亚油酸(瞬时的,作用8小时);3)亚油酸(作用48小时);4)13-HPODE(瞬时的,作用8小时);5)TNF-α(100U/ml,作用4小时)。
图6是一个放射自显影的图示,表明多不饱和脂肪酸对VCAM-1mRNA的诱导是不依赖于蛋白合成的。HAEC受油酸(7.5μM)或花生四烯酸(7.5μM)作用4小时,分别在有或没有放线菌酮(10μg/ml)的情况下,然后再按图5的说明处理。
图7是一个放射自显影的图示,表明亚油酸通过氧化-还原敏感的NF-κB类似因子诱导VCAM-1启动子的转录激活。HAEC按一定比例传代,使其在100mm组织培养碟的汇合率约达60%。采用规范的技术,通过磷酸钙共沉淀途径,用30μg p288 VCSMCAT,p85VCAMCAT或pSV2CAT质粒转染HAEC细胞。经过24小时的恢复期后,HAEC用50μM PDTC进行预处理或不处理,30分钟后,用亚油酸(7.5μM)作用或将TNF-α(100U/ml)直接加到培养碟内。18小时后,采用0.25M Tris pH8.0快速冻融法制备细胞提取物。每一提取物蛋白都要进行氯霉素乙酰转移酶(CAT)测活分析。(测法如前所述[Ausubel,1989](Ac,乙酰化的;N,非乙酰化的氯霉素)。
图8是丙烯酰胺凝胶平板电泳的图示,表明被抗氧化剂PDTC所阻断的NF-κB类似因子的DNA结合活性可以被多不饱和脂肪酸激活。在含有4%FBS(如图1所述)培养中已经汇合的HAEC用PDT(50μM)预处理30分钟,或不用PDTC。然后分别用亚油酸(7.5μM),油酸(7.5μM)或TNFα(100U/ml)处理3小时。取5μg核提取物与32P标记的双链wt VCAM孵育,在4%非变性丙烯酰胺凝胶上进行片段大小分离,与放射自显影胶片在-70℃曝光18小时。两条带A和C代表NF-κB类似的结合活性。在对照组细胞(未处理的)实验观察到弱的B带。
图9A和9B是在PDTC存在或不存在的情况下,花生四烯酸和15-HPETE的相关硫代巴比妥酸反应性物质(O.D.532nm)的棒图。硫代巴比妥酸反应性分析(TBARS)用以测量某物质在无细胞,无培养基体系中的氧化能力。
图10是mRNA的放射自显影图,mRNA按下述方法制备,与32P标记的人VCAM-1特异性的cDNA(A道),E-选择素(ELAM-1)特异性cDNA(B道),或ICAM-1特异性cDNA(C道)杂交。下面,先用50μM吡咯烷二硫代氨基甲酸钠(PDTC)预处理30分钟,在50μM PDTC持续作用的同时,用IL-1b(10U/ml)作用于HUVE(人脐静脉)细胞。对照组进行相同的操作,只是不用PDTC处理。在特定的时间,提取总RNA,取20μg样品进行1.0%变性琼脂糖-甲醛凝胶电泳的片段大小分离,转移到硝酸纤维素膜,按上述方法进行杂交并通过放射自显影来显示。1道,0小时;2,4,6,8道,只用OL-1分别作用2,4,8和24小时;道3,5,7,9,IL-1和PDTC共同作用,作用时间分别是2,4,9和24小时。
图11是mRNA的放射自显影图,mRNA按下述方法制备,与32P标记的人VCAM-1特异性cDNA(A道),E-选择素(ELAM-1)特异性cDNA(B道),或ICAM-1特异性cDNA(C道)杂交。用特定浓度的PDTC对HUVE细胞进行预处理,然后在PDTC存在下用IL-1b作用4小时,用Northern杂交分析VCAM-1 mRNA和积累。1道,对照;2道,IL-1(10u/ml),3道,IL-1b+PDTC(0.05μM);4道,IL-1LB+PDTC(0.5μM);5道,IL-1b+PDTC(5.0μM);6道,IL-1b+PDTC(50.0μM);7道,IL-1b+PDTC(100μM)。
图12是mRNA的放射自显影图示,mRNA按下述方法制备,与32P标记的人VCAM-1特异性的cDNA(A道),E-选择素(ELAM-1)特异性的cDNA(B道)或ICAM-1特异性的cDNA(C道)杂交。HUCE细胞按图9所述用50μM PDTC预处理,再用下面的试剂处理4小时,来分析VCAM-1(A道)和ICAM-1(B道)mRNA的积累。1道-TNFα(100U/ml),2道-TNFα+PDTC,3道-脂多糖(LPS)(100ng/ml),4道-LPS+PDTC,5道-poly(I∶C)(100mg/ml),6道-poly(I∶C)+PDTC。
图13是在PDTC存在(黑棒)或不存在(白棒)情况下,并且施加多种类型的诱导刺激后细胞表面VCAM-1和胞内ICAM-1相对的表达图。汇合的HUVE细胞用50μM PDTC预处理30分钟,或不处理(只不CTL),然后在PDTC存在或不存在(仅CTL)的情况下,用指定的试剂作用一定的时间。确定细胞表面分子的表达是通过VCAM-1特异性(439)和ICAM-1特异性(84H10)的鼠单克隆抗体与之进行初级结合,然后与辣根过氧化物酶标记的羊抗-鼠(IgG)进行次级结合。
图14是人脐静脉内皮细胞被TNFα激活后,表面VCAM-1的表达(O.D.595nm)对各种抗氧化剂浓度的关系图(PDTC是N-吡咯烷二硫代氨基甲酸钠;DETC是N,N-二乙基-二硫代-N-甲酸钠,也即二乙基二硫代氨基甲酸钠;NAC是N-乙酰半胱氨酸;DF是去铁敏)。
图15是人脐静脉内皮细胞被TNF-α激活后,在存在特定量的抗氧化剂的情况下,表面VCAM-1的表达的相关图。(PDTC是N-吡咯烷二硫代氨基甲酸钠;DIDTC是N,N-二乙基-二硫代-N-甲酸钠;SarDTC是N-甲基-N-羧甲基-二硫代-N-甲酸钠;IDADC是N,N-二(羧甲基)-二硫代-N-甲酸三钠;MGDTC是N-甲基-D-葡糖胺-二硫代-N-甲酸钠;MeOBGDTC是N-(4-甲氧苄基)-D-葡糖胺-二硫代-N-甲酸钠;DEDTC是N,N-二乙基-二硫代-N-甲酸钠;Di-PDTC是N,N-二异丙基-二硫代-N-甲酸钠;NAC是N-乙酰半胱氨酸)。
图16是在PDTC存在或不存在的情况下,Molt-4细胞与TNFα(100U/ml)刺激或不刺激的HUVE细胞结合百分率图。
图17是下面一些活性二硫代氨基甲酸盐的化学结构图:吡咯烷-二硫代-N-甲酸钠;N-甲基-N-羧甲基-二硫代-N-甲酸钠;N,N-二(羧甲基)-二硫代-N-甲酸三钠;N-甲基-D-葡糖胺-二硫代-N-甲酸钠;N,N-二乙基-二硫代-N-甲酸钠(二乙基二硫代氨基甲酸钠)和N,N-二异丙基-二硫代-N-甲酸钠。
图18是一个棒图,显示了BSA和13-HPODE偶联荧光加合物的形成,测量时以荧光强度单位比PDTC的微摩尔浓度。在PDTC存在的情况下,1μM的13-HPODE与200μg的BSA孵育6天,荧光在330-360nM激发后在430-460nM测量。
图19显示的是PDTC时BSA和ox-PUFA形成偶联荧光加合物的影响,以波长(nm)和PDTC浓度之间的函数关系来表示,当PDTC浓度增加时,荧光加合物的量降低。
图20显示了PDTC对辣根过氧化酶氧化LDL的影响,以不同PDTC浓度下O.D.值(234nm)的增加与时间(分钟)的比来表示。发现,经过一段时间的孵育,PDTC可以浓度依赖性的方式抑制HRP(辣根过氧化酶)对LDL的氧化。
图21显示了PDTC对细胞因子诱导人主动脉内皮细胞ox-PUFA形成的影响。如图所示,TNF-α和IL-1β使亚油酸氧化成为ox-亚油酸,而PDTC可以明显地防止氧化。
发明详述I.定义
这里所用的多不饱和脂肪酸(也即“PUFA”)指的是有至少两个链烯键的脂肪酸(典型地是C8-C20)包括但并不限于亚油酸(C18Δ9,12),亚麻酸(C18Δ6,9,12),花生四烯酸(C20Δ5,8,11,14)和二十碳三烯酸(C20Δ8,11,4)。
氧化多不饱和脂肪酸指的是指不饱和脂肪酸中至少有一个链烯键已被转化为氢过氧化物。非限制的例子如:13-HPODE15-HPETE
这里所用的烷基这个词,除非特别指出,指的都是饱和的直链、支链或环状(在C5或更多碳链的情况下)C1到C10(的烯(或低级的烷基即C1~C5),具体地说包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、环戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、3-甲基戊基、2,2-二甲基丁基、2,3-二甲基丁基。烷基的任一碳原子都可被选自如下的一个或多个部分取代:羟基、氨基,或者是单的或是双取代的氨基,其中,取代基可以是烷基、芳香基、烷芳香基或芳香烷、芳香基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸盐、磷酸、磷酸盐、或膦酸盐,或者是未受保护的,或者如果需要是被保护的,正如本领域技术人员所知道的,如在Greene等书中所介绍的“有机合成中的保护基团”。John Wiley和Sons,第二版,1991。
链烯基这一术语,除了特别指出,在这里指的是直链、支链或环状的含2-10个碳原子,至少有一个是双键的烃。
炔基这一术语,除了特别指出,在这里指的是直链或支链的烃,有2~10个碳原子,并至少有一个三键。
烷芳基这一术语指的是至少有一个芳香取代基的烷基。
芳烷基这一术语指的是至少有一个烷基取代基的芳香基。
术语卤代(烷基,烯基或炔基)指的是烷基,烯基或炔基中至少有一个氢原子被卤素原子取代。
这里所说的芳香基,除非特别指出,指的是苯基,联苯基或萘基,尤其是指苯基,芳香基可被任选自下面的一个或多个基团部分取代,包括烷基、羟基、氨基、烷基胺、芳基胺、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸盐、磷酸、磷酸盐或膦酸盐,CO2H或它的药用盐、CO2(烷基、芳香基、芳烷基或烷芳基),或葡糖胺,或是未受保护,或者如果必需要受到保护,正如本领域专业人员所知的,如Greene等书中所教的“有机合成中的保护基团”。John Wiley和Sons,第二版,1991。
这里所所说的烷氧基除非特别指出,指的是-O-烷基结构的一部分。
这里所用的酰基一词指的是分子式(CO)R’中的一个基团,其中R’可以是烷基,芳基,烷芳基或芳烷基基团。
这里所用的杂芳基或杂芳族化合物术语指的是芳族部分的芳环上至少有一个硫原子,氧原子或氮原子。非限制性的例子包括:吩嗪、吩噻嗪、呋喃基、吡啶基、嘧啶基、噻吩基、异噻唑基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基(benzothiophenyl)、喹啉基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、吲哚基、异吲哚基、苯并咪唑基、嘌呤基、吗啉基、(carbozolyl)、噁唑基、噻唑基、异噻唑基,1,2,4-噻二唑基、异噁唑基、吡咯基、吡唑基、喹唑啉基、哒嗪基、吡嗪基、肉啉基、2,3-二氮杂萘基、喹喔啉基、黄嘌呤基、次黄嘌呤基、均三唑并吡啶基、咪唑并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、腺嘌呤、N6-烷基嘌呤、N6-苯甲基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤、N6-乙炔基嘌呤、N6-酰基嘌呤、N6-羟烷基嘌呤、N6-硫代烷基嘌呤、胸腺嘧啶、胞嘧啶、6-氮杂嘧啶、2-巯基嘧啶、尿嘧啶、N5-烷基嘧啶、N5-苯甲基嘧啶、N5-卤代嘧啶、N5-乙烯基嘧啶、N5-炔基嘧啶、N5-酰基嘧啶、N5-羟烷基嘌呤、N6-硫代烷基嘌呤,以及异噁唑基。杂芳基可以用来替代上述芳基。杂芳族化合物可根据预期目的部分或全部氢化。非限制性的例子为,二氢吡啶可取代吡啶。杂环碱中功能性氧原子及氮原子可以在反应序列中作为必需或预期原子而保护起来。适当的保护基团为技术熟练者所熟知,包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、三苯甲游基甲基和烷基等,以及诸如乙酰基、丙酰基、磺酰基及对甲苯甲酰磺酰基等酰基基团。
羟烷基用在这里指的是一到六个碳原子的烷基中,不管哪个碳原子上所连的氢原子,但至少要有这样一个氢原子由羟基所取代。
硫羟抗氧化剂指的是含有硫并能阻碍氧化反应的化合物。
药用衍生物指的是活性复合物的衍生物,当用于受体时,可以直接或间接地产生亲代复合物,或者本身可以显示出活性。
“药用阳离子”指的是带有正电荷的有机或无机基团,能用来与药剂偶联,如在盐中做配位阳离子。药用阳离子对本领域的专业人员来说并不陌生,包括但并不限于钠、钾和季胺。
“生理上可切割的离去基团”指的是在体内可以从它所连接的分子上切去的基团,包括但并不限于有机或无机阴离子,药用阳离子,酰基(包括但并不限于(烷基)C(O),包括乙酰基、丙酰基和丁酰基)、烷基、磷酸盐、硫酸盐和磺酸盐。
“对映体富集组合物或化合物”指的是该组合物或化合物中,某单一对映体的重量百分比至少是95%,优选是至少97%、98%、99%,甚至100%。
氨基酸这一词包括合成的或自然产生的氨基酸。包括但并不止这些,如丙氨基、缬氨基、亮氨基、异亮氨基、脯氨基、苯丙氨基、色氨基、甲硫氨基、甘氨基、丝氨基、苏氨基、半胱氨基、酪氨基、天门冬酰氨基、谷酰氨基、天门冬氨基、谷氨基、赖氨基、精氨基和组氨基。
这里所用的连接部分指的是任一个二价的连有两个化学残基的基团,包括但并不限于烷基、烯基、炔基、芳香基、多(亚烷基氧基)基(如-[(CH2)nO-]n-、-C1-6烷氧基、-C1-10烷基-、-C1-6烷硫基-C1-10烷基-、-NR3-和-(CHOH)nCH2OH,其中n可以是0、1、2、3、4、5或6。II.氧化和未氧化的多不饱和脂肪酸作为VCAM-1表达的直接中介者的鉴定
为了鉴定PUFA或氧化的PUFA是否可以作为内皮细胞基因表达的直接免疫调节子,早期传代培养的人主动脉内皮细胞(HAEC)在培养基和血清中培养8小时,再加饱和脂肪酸(硬脂酸),单不饱和脂肪酸(油酸),和多不饱和脂肪酸(亚油酸和花生四烯酸);还有亚油酸的氢过氧化物(13-HPODE)或花生四烯酸的氢过氧化物(15-HPETE)。还可以给HAEC加细胞因子-肿瘤坏死因子-α。
在不同的时间用亚油酸和13-HPODE分别作用于HAEC达48小时,然后用ELISA反应(酶联免疫吸附法)分析细胞表面VCAM-1的表达。结果与同样的作用时间,TNF-α(100U/ml)作用下的HAEC细胞相比较。与亚油酸或13-HPODE孵百后的HAEC细胞,VCAM-1表达受到短暂诱导。表达在作用8-9个小时时达到高峰,在24小时极大地表达然后到48小时已经下降。亚油酸和13-HPODE诱导VCAM-1表达的动力学与TNF-α的作用类似,因此多不饱和脂肪酸诱导VCAM-1的机制与TNF-α很相似。
也做了8小时时亚油酸和13-HPODE诱导VCAM-1基因表达的剂量反应。发现7.5μM是亚油酸和13-HPODE诱导产生大量VCAM-1基因表达峰的最低剂量。
接下来观察了内皮细胞与多不饱和脂肪酸短时间孵育是否也诱导ICAM-1和E-选择素的表达。发现多不饱和脂肪酸亚油酸和花生四烯酸对细胞表达基因表达的诱导大约相当于TNF-α诱导的VCAM-1基因表达的59%。值得注意的是,这些脂肪酸都不能诱导ICAM-1和E-选择素的表达。相反,饱和脂肪酸硬脂酸和单不饱和脂肪酸油酸则不诱导VCAM-1、ICAM-1和E-选择素的表达。还观察到亚油酸和花生四烯酸的氧化产物13-HPODE和15-HPETE与HAEC细胞孵育可诱导其VCAM-1基因的表达。
为了观察由多不饱和脂肪酸及其氧化产物对内皮细胞产生的氧化应激是否通过氧化还原敏感的机制来诱导VCAM-1基因表达,用抗氧化剂PDTC(吡咯烷二硫代氨基甲酸盐)50μM预处理HAEC约30分钟,然后细胞分别与亚油酸、花生四烯酸、13-HPODE和15-HPETE(都是7.5μM)孵育8小时。表明PDTC抑制多不饱和脂肪酸及其氧化产物对VCMA-1表达的诱导。这就说明诱导是由氧化信号分子介导的,当分子的氧化被阻断时(即氧化反应不能发生),被逆转时(也即信号分子被还原),或它们与靶蛋白的互作也许是通过氧化还原复合物而被阻碍,这时候诱导也就受阻。
为了确定PUFAs及其氧化产物对VCAM-1的选择性诱导是否是在mRNA水平上,用亚油酸和13-HPODE与HAEC孵育。亚油酸和13-HPODE诱导VCAM-1 mRNA累积近似于TNF-α的诱导水平。相比之下,HAEC与亚油酸和13-HPODE孵育后对ICAM-1和E-选择素没有任何mRNA水平的诱导。类似的实验都是在细胞表面有所发现。这些结果表明翻译前调节机制介导了多不饱和脂肪酸及其氧化产物对VCAM-1基因表达的诱导。
还想确定一下多不饱和脂肪酸是作为首要信号分子还是通过包括细胞因子IL-4的调节蛋白来介导VCAM-1基因表达的诱导。为了观察PUFAs如亚油酸诱导的VCAM-1基因表达和合成过程中是否包含新合成的蛋白如IL-1,让HAEC与13-HPODE(7.5μM)孵育,然后添加蛋白合成抑制剂放线菌酮。HAEC与13-HPODE孵育并加放线菌酮抑制后,VCAM-1 mRNA的累积并不受抑制。HAEC与亚油酸,花生四烯酸及其氧化产物共孵育后IL-4的产生也进行了测量,如ELISA描述的那样来确定。发现这些PUFAs或它们的氧化产物与HAEC孵育并不能增加IL-4的量。
以前通过缺失和杂合启动子的实验发现,内皮细胞中细胞因子和非细胞因子激活VCAM-1基因表达至少部分是通过两个NF-κB类似因子。为了确定多不饱和脂肪酸诱导人VCAM-1启动子转录激活也是通过相似的机制,嵌合的报告基因p288 VCAM-CAT,含有携带的人VCAM-1启动子的-288~+22序列,对HAEC进行瞬时转染。加亚油酸(7.5μM)能诱导VCAM-1启动子,亚油酸对VCAM-1启动子活性的诱导超过对照的两倍,大约是TNF-α诱导的最大信号的60%。用小的细胞因子可诱导的VCAM-1基因的启动子(p85 VCAM-CAT),含有NF-κB类似位点的-77~63bp序列,这实验也得出相似的结果。用持续表达的p5/2 CAT构建体,则亚油酸和TNF-α对启动子活性都没有任何影响。上述两种可由亚油酸诱导的VCAM-1启动子构建物中转录激活的诱导可以被PDTC抑制。这些数据表明,与TNF-α类似,多不饱和脂肪酸如亚油酸诱导VCAM-1的转录激活是通过NF-κB类似的氧化-还原敏感的机制。
为了确定多不饱和脂肪酸和它们的氧化产物对VCAM-1启动子活性的调节是否是通过NF-κB类似的转录调节因子作用,分析了HAEC核提取物中一段双链寡核苷酸的DNA结合活性,其中包含-77~63bp的VCAM-1类似NF-κB启动子的序列。如图7所示,A和C带代表亚油酸(7.5μM)作用3个小时NF-κB类似的活性的诱导。细胞因子TNF-α(100U/ml)作用也可以得出近似的结果。对照细胞(未处理)则可观察到弱带B。用单不饱和脂肪酸油酸作用则观察不到任何NF-κB类似的结合活性。用PDTC预处理细胞30分钟,亚油酸激活的A和C复合物的DNA结合活性受到抑制。这些发现类似于以前报道过的HUVEC中VCAM-1基因表达的激活,这是通过抑制NF-κB类似的DNA结合蛋白的激活而实现的。
实施例1:氧化和非氧化的多不饱和脂肪酸对VCAM-1基因表达激活
的动力学的影响
人主动脉内皮细胞培养于96孔板,与亚油酸(7.5μM),13-HPODE(7.5μM)或TNF-α(100U/ml)孵育,作用5个不同的时间,达48小时。HAEC细胞购自Clonetics公司(Boston,MA),在199培养基中培养并添加20%胎牛血清(FBS),16U/ml的肝素,10U/ml的上皮生长因子,50μg/ml内皮细胞生长补充物,20mM L-谷氨酰胺,100U/ml的青霉素和100μg/ml的链霉素。实验前一天,细胞换成4%FBS的培养基培养。汇合的HAEC与TNF-α(100U/ml),或硬脂酸、油酸、亚油酸、亚麻酸,或花生四烯酸(7.5μM)作用达48小时。用不同剂量的亚油酸或13-HPODE作用8小时(1~60μM)进行类似的研究(图2)。通过TMB在450nm下的比色转变剂来定量。实验进行了3个平行(n=4,对每个实验值来说)。*表示实验值与对照间有差异(P<0.05)。
如图1所示,亚油酸和13-HPODE可诱导VCAM-1的表达。作用10个小时后,油酸和13-HPODE所诱导的细胞表面VCAM-1的量大于细胞因子TNF-α所诱导的50%。
如图2所示,油酸和13-HPODE对VCAM-1的诱导是浓度敏感性的。在这些化合物的浓度在2-10μM之间时,细胞表达诱导的VCAM-1的量呈现急剧上升,之后诱导量基本恒定,持续到至少100μM时。应该注意到图2所示的PUFA的浓度是在已知的HAEC内源性PUFA基础上附加的。实施例2:多不饱和脂肪酸诱导VCMA-1的基因表达,但不诱导ICAM
-1和E-选择素
HAEC中VCAM-1在细胞表面的表达及ICAM-1和E-选择素的表达用ELISA法测定。HAEC购自Clonetics公司(California),在199培养基中培养,其中添加有20%胎牛血清(FBS),16U/ml的肝素,10U/ml的表皮生长因子,50μg/ml内皮细胞生长添加物,2mM L-谷氨酰胺,100U/ml青霉素和100μg/ml的链霉素。实验前一天,细胞换入含4%FBS的培养基。汇合的细胞与TNF-α(100U/ml),或硬脂酸、油酸、亚油酸、亚麻酸或花生四烯酸(7.5μM)共孵育8小时,或不与以上化合物孵育。对细胞表面A)VCAM-1,B)ICAM-1和C)E-选择性的表达进行了测定,用VCAM-1特异性,ICAM-1特异性和E-选择性特异性的鼠抗体作一抗,以辣根过氧化酶标记的羊-抗鼠IgG作二抗,以TMB 450nm下的比色变化来定量。实验进行三组平行(每组实验值n=4)。*表示测量值与对照有差异(P<0.05)。
如图3所示,亚油酸、亚麻酸和花生四烯酸大幅度诱导VCAM-1的表达,但不诱导ICAM-1和E-选择素在细胞表面的表达。硬脂酸和油酸则不诱导VCAM-1,ICAM-1或E-选择素的表达。TNF-α则很明显地诱导以上三种细胞表面分子的表达。实施例3:抗氧化剂PDTC抑制多不饱和脂肪酸和它们的氧化产物对
VCAM-1的诱导
汇合的HAEC在PDTC存在(吡咯烷二硫代氨基甲酸钠,50μM)或不存在的情况下预处理30分钟。然后细胞与TNF-α(100U/ml),亚油酸或花生四烯酸(7.5μM),或脂肪酸氢过氧化物1 3-HPODE(7.5μM)或15-HPETE(7.5μM)共孵育8小时。如实施例1所示用ELISA法测定HAEC细胞表面VCAM-1表达。实验进行了三组平行(每组实例值中n=4)。*表示测量值与对照有差异(P<0.05)。
如图4所示,亚油酸,13-HPODE,花生四烯酸和15-HPETEVCAM-1诱导受PDTC抑制。实施例4:亚油酸和13-HPODE对VCAM-1瞬时诱导
用亚油酸(7.5μM)或13-HPODE(7.5μM)作用于HAEC。提取总RNA,取20μg在1.0%的琼脂糖-甲醛变性凝胶电泳进行片段分离。转移到硝酸纤维素膜,与32P标记的人A)VCAM-1特异性或B)β-肌动蛋白特异性cDNA杂交,通过放射自显影观察结果。漂洗后,膜与X-胶片在-70℃下加感光屏曝光24小时。泳道辨别:1)对照;2)亚油酸(瞬时,8小时);3)亚油酸(作用48小时);4)13-HPODE(瞬时,8小时);5)TNF-α(100U/ml,4小时)。
如图5所示,亚油酸和1 -HPODE都是在8小时诱导VCAM-1mRNA的产生。48小时后,亚油酸不再诱导VCAM-1 mRNA。实施例5:PUFAs对VCAM-1 mRNA的诱导不依赖于细胞蛋白质的
合成
在放线菌酮(10μg/ml)存在或不存在的情况下,用亚油酸或花生四烯酸(7.5μM)对HAEC作用4小时。提取总RNA,取20μg在1.0%琼脂糖-甲醛变性凝胶上电泳进行片段分离,转移到硝酸纤维素膜,与32P标记的A)人VCAM-1或B)人β-肌动蛋白特异性cDNA杂交,通过放射自显影观察结果。漂洗后,膜与X-胶片在-70℃下加增感屏曝光24小时。
如图6所示,亚油酸和花生四烯酸对VCAM-1的诱导是不依赖于胞内蛋白质合成。实施例6:亚油酸通过氧化-还原敏感的NF-κB类似因子诱导VCAM
-1启动子的转录激活
HAEC按一定比例传代,使在100-mm组织培养碟中汇合率约达60%。采用磷酸钙共沉淀法标准操作技术,用30μg p288 VCAMCAT,p85 VCAMCAT或pSV2CAT质粒转染HAEC,经过24小时的恢复阶段,用50μM PDTC预处理HAEC,30分钟后用亚油酸(7.5μM)作用或将TNF-α(100U/ml)直接加入培养碟。18小时后,通过在0.25MTris,pH8.0中冻融的方法制备细胞提取物。每个细胞提取物蛋白样品都进行氯霉素乙酰转移酶(CAT)活性分析。(Ac,乙酰化的;N,非乙酰化的氯霉素)。
图7显示了本实验的结果,亚油酸通过氧化-还原敏感的NF-κB类似因子诱导VCAM-1启动子的转录激活。这些结果类似于细胞因子如TNF-α对VCAM-1启动子的激活。这就表明,PUFAs通过氧化的中介物,而这个中介物也介导细胞因子对VCAA-1的激活。实施例7:被抗氧化剂PDTC阻断的多不饱和脂肪酸对NF-κB类似
的DNA结合活性的激活
汇合的HAEC培养于含4%FBS(如实施例1所述)的培养基中,用PDTC(50μM)预处理30分钟,然后用亚油酸,油酸(7.5μM)或TNF-α(100U/ml)作用3小时。取5μg核提取物与32P标记的双链wtVCAM孵育,在4%纯丙烯酰胺凝胶上进行片段分离,在-70℃与放射自显影膜曝光18小时。两条带A和C代表NF-κB类似的结合活性。对照细胞(未处理)可以观察到弱带B。
图8表明亚油酸以氧化-还原敏感的方式诱导NF-κB结合到VCAM-1启动子的结合活性。这很类似于细胞因子TNF-α,表明它们之间相似的作用机制。TNF-α可能是通过ox-PUFA介导的机制来诱导VCAM-1。实施例8:通过未氧化和氧化的(15-HPETE)花生四烯酸蛋白无细
胞,无培养液的氧化体系
图9A和9B两个棒图显示的是在PDTC存在或不存在的情况下,花生四烯酸和15-HPETE相应硫代巴比妥酸反应性物质(O.D.532nm)。硫代巴比妥酸反应性分析(TBARS)用来测量无细胞,无培养基体系中物质的氧化能力。如图所示,花生四烯酸和15-HPETE都显示出很强的TBARS活性,而这种活性可被PDTC抑制。III治疗VCAM-1介导的疾病的方法
多不饱和脂肪酸和它们的氧化产物是选择性的,氧化-还原敏感的免疫调节因子这一发现为由VCAM-1或氧化-还原敏感基因介导的疾病的治疗提供了依据。
于是提出了以下疾病的治疗方法,动脉粥样硬化,血管成形术后再狭窄,冠状动脉病,绞痛,其它心血管病及由VCAM-1介导的非心血管性的炎症。方法包括移去或降低氧化多不饱和脂肪酸的浓度,或阻止氧化多不饱和脂肪酸的形成,包括但不限于氧化亚油酸,亚麻酸和氧化花生四烯酸。在另-种实施方案中,这些疾病的治疗方法包括阻止PUFA或氧化PUFA与介导VCAM-1表达的蛋白或多肽发生作用。
抑制VCAM-1表达可由几种途径来完成,包括用抗氧化剂阻止多不饱和脂肪酸的氧化,也可以对PUFA转化为ox-PUFA的代谢途径进行体内修饰,细节如下所述。1.抗氧化剂的施用
任何化合物,如果能还原ox-PUFA或能抑制PUFA的氧化,相对无毒并且是生物上可接受的,或经过修饰后可转变为生物可接受的,都可以用于治疗中。本领域内一种常规方法,通过标准的操作技术,可以很容易地检验出某化合物是否能还原ox-PUFA或抑制PUFA的氧化。
二硫代羧化物抗氧化剂
已经发现二硫代羧化物有益于动脉粥样硬化,其它心血管疾病及炎症的治疗。二硫代羧化物,包括二硫代氨基甲酸盐可用来阻断细胞包括内皮细胞表达VCAM-1的能力,或可抑制氧化-还原敏感基因或激活由氧化-还原敏感途径抑制的基因。
至少有一种化合物吡咯烷二硫代氨基甲酸盐(PDTC),它可以在小于1.0μM的浓度下抑制VCAM-1基因表达。这个化合物体现出对增殖或不正常分裂的血管平滑肌细胞的选择抑制作用,另-二硫代氨基甲酸盐N-甲基-N-羧甲基-二硫代-甲酸钠也能抑制VCAM-1的表达,但对ICAM-1没有明显影响,对不正常分裂的血管平滑肌细胞没有选择性毒性。
已经发现吡咯烷二硫代氨基甲酸盐并不明显地阻断ELAM-1或ICAM-1的表达,因此用这个化合物来治疗就不会反过来影响由ELAM-1或ICAM-1介导的炎症反应。这就避免了总体免疫抑制。这也可能避免由于已知的能表达这些粘附分子的其它类型的细胞中这种粘附分子普遍受到抑制而产生的系统复杂性。其它药用PDTC的盐也是心血管疾病和炎症等的有效治疗剂。
二硫代氨基甲酸盐是转运金属螯合剂,临床上用来解重金属中毒症。Baselt,R.C.,F.W.J.Sunderman等,(1977),“二乙基二硫代氨基甲酸钠,D-青霉胺和三乙撑四胺对大鼠急性羰基镍毒的抗毒效应比较”。Res Commun Chem Pathol Pharmacol 18(4):677-88;Menne,T.和K.Kaaber(1978),“用螯合剂治疗镍过敏反应引起的汗疱”。接触性皮炎4(5):289-90;Sunderman,F.W.(1978),“对汞蒸汽中毒的治疗试剂的临床反应”Ann Clin Lab Sci 8(4):259-69;Sunderman,F.W.(1979),“二乙基二硫代氨基甲酸钠(dithiocarb)对急性羰基镍毒的疗效”。Ann Clin Lab Sci 9(1):1-10;Gal,G.R.,A.B.Smith等,(1981),“二乙基二硫代氨基甲酸盐对急性镉中毒的治疗”Ann Clin Lab Scill(6):476-83;Jones,M.M.和M.G.Cherian(1990),“寻找慢性镉中毒的螯合拮抗剂”Toxicology 62(1):1-25;Jones,S.G.,M.A.Basinger等。(1982),“二乙基二硫代氨基甲酸盐和EDTA作为急性镉中毒解毒剂的比较”Res Commun Chem Pathol Pharmacol 38(2):271-8;Pages,A.,J.S.Casas等。(1985),“二硫代氨基甲酸盐在重金属中毒中的作用”:N,N-二(1-羟乙基)二硫代氨基甲酸盐与Zn(II),Cd(II),Hg(II),CH3Hg(II)和C6H5Hg(II)形成的复合物。J.Inorg Biochem 25(1):35-42;Tandon,S.K.,N.S.Hashmi,等。(1990),“取代的二硫代氨基甲酸盐的铅螯合效应”。Biomed Eviron Sci3(3):299-305。
二硫代氨基甲酸盐用于顺-铂化疗的辅助药物以预防肾毒性。Hacker,M.P.,W.B.Ershler,等。(1982),“安太布斯(四乙基二硫化四烷基秋兰姆)和二乙基二硫代氨基甲酸盐对小鼠膀胱毒的疗效和环磷酰胺的抗肿瘤活性”。Cancer Res 42(11):4490-4。Bodenner1986#733;Saran,M.和Bors,W.(1990)。“体内基团反应--综述”。Radiat.Environ.Biophys.29(4):249-62。
目前用于治疗酒精滥用的二硫代氨基甲酸盐是安太布斯(disultiram),二乙基二硫代氨基甲酸盐的二聚体。它可以抑制肝脏醛脱氢酶。Inoue,K.,和Fukunaga等,(1982)。“安太布斯(disulfiram)及其还原产物二乙基二硫代氨基甲酸盐对人红细胞醛脱氢酶的影响”。Life Sci 30(5):419-24。
已有报道说二硫代氨基甲酸盐抑制爱滋病毒(HIV)复制,也能加速T细胞亚群的成熟。这已经用于临床尝试,即二乙基二硫代氨基甲酸盐用于爱滋病患者群。Reisinger,E,等,(1990)“二硫代羧化物(dithiocarb)对爱滋病毒扩展的抑制”。Iancet 335:679。
二硫代羧化物指的是结构式为A-SC(S)-B的化合物,属于硫醇(thiol)抗氧化剂类物质,换个说法是指碳化二硫醇(carbodithiols)或碳化二硫代化物(carbodithiolates)。-SC(S)-部分似乎对治疗活力很必要,A和B则可以是任意不相互影响化合物疗效或毒性的基团。
另一种实施方案,二硫代氨基甲酸盐中一个或两个硫原子可由硒原子取代。硒原子取代硫原子在某些情况下可以降低分子毒性,因此更可能被病人耐受。
A和B可由本领域内任一普通的技术人员进行选择,赋于它们所需的特征,包括大小,电荷,毒性及稳定性,(包括酸性环境如胃,或碱性环境如肠道中的稳定性)。A和B的选择对化合物组织分布和药物动力学也有很重要影响。总的来说治疗心血管疾病,希望化合物能积累或定位于含有血管内皮细胞的动脉内膜层。并希望化合物最好能通过肾分泌而去除。
使用二硫代羧化物在药学上的优点是它在体内不能被硫酯酶切割,因此在体内能体现持久的半衰期。
在一个优选的实施方案中,A是氢原子或药学上可接受的阳离子,包括但并不限于钠、钾、钙、镁、铝、锌、铋、钡、铜、钴、镍或镉;成盐有机酸,特别是羧酸,包括但并不限于乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、pamoic酸、藻酸、聚谷氨酸、萘磺酸、萘二磺酸或聚半乳糖醛酸;或由氨或其它含氮的碱基形成的阳离子,包括但不限于含氮杂环,或通式NR4R5R6R7的一部分,其中R4、R5、R6和R7分别是氢原子,C1-6线性,有分枝或(在C4-6的情况下)环状的烷,羟基烷(C1-6)(其中1个或多个羟基可位于任一碳原子),或芳香基,N,N-二苯基-1,2-乙二胺,D-葡萄糖胺,胆碱,四乙胺,或1,2-乙二胺。
在另一种实施方案中,A可以是一个生理上能切割的可离去基团,它能在体内从它所连接的分子上被切去,包括但并不限于酰基(包括乙酰基,丙酰基和丁酰基),烷基,磷酸盐,硫酸盐或磺酸盐。在一种实施方案中,B是烷基,链烯基,炔基,烷芳基,芳烷基,卤代烷基,卤代链烯基,卤代炔基,芳香基,烷芳基,氢原子,C1-6烷氧基-C1-10烷基,C1-6烷硫基-C1-10烷基,NR2R3,-(CHOH)nCH2OH,其中n是0,1,2,3,4,5或6,-(CH2)2CO2R1,包括烷基乙酰基,烷基丙酰基,和烷基丁酰基,或羟基C1-6烷基, (其中一个或多个羟基可位于任一碳原子)。
在另一种实施方案中,B是NR2R3,其中R2和R3分别是烷基;-(CHOH)n(CH2)nOH,其中n是0,1,2,3,4,5或6;-(CH2)nCO2R1, -(CH2)nCO2R4,羟基(C1-6烷基;链烯基)包括但不限于乙烯基,烯丙基,和CH3CH=CH-CH2(H2);烷基(CO2H),链烯基(CO2H),炔基(CO2H),或芳香基,其中芳基可由上面所述被取代,尤其是NO2,CH3,t-丁基,CO2H,卤代基或p-OH基;或R2和R3能一起组成一个桥如-(CH2)m-,其中m是3,4,5或6,其中R4是烷基,芳香基,烷芳基或芳烷基,包括乙酰基、丙酰基或丁酰基。 .
在另一个实施方案中,B可以是杂环或烷基杂环基团。杂环可以选择性地部分或全部地被氧化。部分例子如上面所列的那些,包括吩嗪、吩噻嗪、吡啶和二氢吡啶。
在又一个实施方案中,B是药学上有活性的化合物或药物的残基。药物这一词指的是任何内用或外用可以作为药物的物质,用来治疗,治愈或预防疾病或紊乱。
非限制性的治疗或预防心血管疾病的药物例子包括抗氧化剂如普罗布考;尼古丁酸;阻碍血小板粘连的试剂如阿司匹林;抗血栓试剂如苄丙酮香豆素钠;钙通道阻断剂如维拉帕米,地尔硫和硝苯地平,血管紧张素转化酶(ACE);抑制剂如卡托普利(captopril)和依那普利(enalopril);β-阻断剂如propanalol,terbutalol,和拉贝洛尔,非甾醇类的抗炎症剂如布洛芬,吲哚美辛,非诺洛芬,甲芬那酸,氟芬那酸,及舒林酸或皮质甾醇。-C(S)SA基团可以直接连到药物上或通过任意合适的连接部分。
在另一个实施方案中,二硫代氨基甲酸盐是某氨基酸的衍生物,结构是AO2C-R9-NR10-C(S)SA,其中R9是二价的B部分,是连接部分,或任意天然氨基酸的内部残基(如丙氨酸的CH3CH,甘氨酸的CH2,赖氨酸的CH(CH2)4NH2,诸如此类)。R10是氢原子或低级烷。
B也可以是个聚合物,上面连有1个或多个二硫代氨基甲酸盐基团,或是直接连上去或是通过合适的连接(linking moiety)部分。二硫代氨基甲酸盐在体内条件下,经过一段合适的时间,可以优先从聚合物上释放出来,有益于治疗。在优选的实施方案中,聚合物本身在体内也是可降解的。生理上可降解或生物可蚀性用在这里指的是在所希望的使用中一段可接受的时间内能溶解或降解的多聚物(通常是指在体内治疗时),通常是小于5年,尤其是一年之内,在pH 6-8的生理溶液中,温度在25-37℃下。在一优选实施方案中,依使用条件在1小时到几星期的一段时间内,聚合物就会降解。
已知的一些可降解的聚合物,非限制性的例子有肽、蛋白、核蛋白、脂蛋白、糖蛋白,合成和天然的多肽和多聚氨基酸,包括但并不限于赖氨酸、精氨酸、天门冬氨酸、天门冬氨酸、半胱氨酸、胱氨酸、谷氨酸、谷氨酰胺、羟基赖氨酸、丝氨酸、苏氨酸和酪氨酸的聚合物和共聚物;多聚原酸酯,包括多聚(α-羟基酸),如聚乳酸、聚羟基乙酸(polyglgcoilc acid),聚(丙交酯和乙交酯),聚酐类,白蛋白或胶原蛋白,含糖单位如乳糖的多糖,和聚己酸内酯,多聚物可以是无规共聚物或嵌段共聚物。
B也可为一个增强二硫代氨基甲酸盐水溶性的基团,例如低级烷基-O-R8,在此R8是-PO2(OH)M+或PO3(M+)2,并且M+是药用的阳离子;C(O)(CH2)2CO2 -M+,或SO3 -M+;低级烷基羰基-低级烷基;羧基-低级烷基;低级烷基氨基-低级烷基;或N,N-二取代氨基-低级烷基,其中的取代基又分别可为低级烷基;吡啶基-低级烷基;咪唑基-低级烷基;咪唑基-Y-低级烷基,其中Y可为硫代或氨基;吗啉基-低级烷基;吡咯烷基-低级烷基;噻唑啉基-低级烷基;哌啶基-低级烷基;吗啉基-低级羟烷基;N-吡咯基;哌嗪基-低级烷基;N-取代哌嗪基-低级烷基,其中取代基是低级烷基,三唑基-低级烷基;四唑基-低级烷基;四唑氨基-低级烷基;或噻唑基-低级烷基。
在另一个实施方案中可以施用如B-C(S)S-SC(S)-B的二聚物。
CH3-CH=CH
H+
选出来治疗动脉粥样硬化和炎症的二硫代羧化物应该有适当的亲脂性,使得它们能位于患病部位。这些化合物在低代谢率区域如脂肪堆积区不会区域化。在治疗心血管病的优选实施方案中,化合物的药物动力学不应该受充血性心脏衰退或肾功能不足的显著影向。
对治疗炎症皮肤病的局部使用来说,所选的化合物应经过规范化,使皮肤能对其充分吸收,以对敷药部位产生疗效。
二硫代羧化物必须是生理上可被接受的。总的来说,化合物治疗指数至少要是2,优选可接受的指数至少要是5或10。治疗指数指的是EC50/IC50,其中EC50是当VCAM-1的表达50%被抑制时化合物的浓度。IC50是对50%的靶细胞造成毒性时的化合物浓度。细胞毒可以通过直接计数细胞来确定,排除苔酚兰染色细胞,或各种代谢活性研究,如3H-TdR掺入,本领域的专业人员对此是很熟悉的。在培养的HUVE细胞,测得的PUTC,对TNF-α诱导的VCAM-1表达的抑制能力除以细胞毒性得出的PUTC的治疗指数大于100。早期对迅速分裂的细胞类型HT-18人神经胶质瘤细胞的研究表明,在大于治疗浓度100倍时仍无任何毒性。安太布斯(Disulfiram),一种二乙基二硫代氨基甲酸盐的口服形式,用于酒精滥用的治疗,当使用得当时,没体现出任何主要的临床毒性。
已知有少数二硫代氨基甲酸盐有遗传毒性。这些化合物不在本发明的考虑范围内,本发明只限于使用生理上可接受的物质。有遗传毒性的二硫代氨基甲酸盐的一个例子是杀真菌剂二甲基二硫代氨基甲酸锌。另外,某些二硫代氨基甲酸盐的抗胆碱酯酶特征可导致神经毒效应。Miller,D.(1982)。“杀虫的氨基甲酸酯的神经毒性”Neurobehav.Toxicol.Teratol.4(6):779-87。
二硫代羧化物用在这里专指,但不限于通式为R1SC(S)NR2R3或R2R3M(S)CS-SC(S)NR2R3的二硫代氨基甲酸盐。其中R1是H或药用阳离子,包括但并不限于钠、钾或NR4R5R6R7,其中R4,R5,R6和R7是彼此独立的氢原子,C1-6是线性,有分枝或环状烷基,羟基C1-6烷基(其中1个或多个羟基可位于烷基的任一碳原子上),或芳香基,并且R2和R3是彼此独立的C1-10线性,有分枝或环状烷基;-(CHOH)n(CH2)nOH,其中n是0,1,2,3,4,5或6;-(CH2)nCO2R1,-(CH2)nCO2R4;羟基(C1-6)烷基,或R1和R3一起搭成桥如-(CH2)m-,其中m是3~6,而其中R4是烷基,芳香基,烷芳基或芳烷基,包括乙酰基、丙酰基或丁酰基。
有用的二硫代氨基甲酸盐的具体例子如图15所示,包括吡咯烷-二硫代-N-甲酸钠,N,N-二(羧甲基)-二硫代-N-甲酸三钠,N-甲基-D-葡萄糖胺-二硫代-N-甲酸钠,N,N-二乙基-二硫代-N-甲酸钠(二乙基二硫代氨基甲酸钠),和N,N-二异丙基-二硫代-N-甲酸钠。
活性二硫代羧化物特别是二硫代氨基甲酸盐或是通过商业渠道购得,或用已知方法制备。
II.生物活性
二硫代羧化物抑制VCAM-1表达的能力可通过不同的方法测量,包括下面实施例9~15中具体讨论的方法。为方便起见,实施例9~11和14~15描述吡咯烷-二硫代-N-甲酸钠(也即PDTC)生物活性的估测。这些实施例并不是要限制本发明的范围。本发明特别包括用上面描述的任一化合物来治疗动脉粥样硬化及其它类型的由VCAM-1介导的炎症和心血管疾病。上面描述的任一化合物都可以很容易地被PDTC所取代,用相似的方法估测活性。
实施例12和13给出了一些二硫代氨基甲酸盐抑制VCAM-1基因表达的能力的数据比较。以下例子说明,权利要求中的二硫代氨基甲酸盐特异性地阻断血管内皮细胞表达VCAM-1,而VCAM-1的表达是在许多已知的在动脉粥样硬化和炎症反应中有活性的信号诱导的。实验方法
细胞培养HUVE细胞是从进行插管的人脐静脉分离得到,用Hanks液灌注以除去血。然后用1%胶原蛋白酶在37℃孵育15分钟,撤去胶原蛋白酶,细胞在M199培养基中培养,其中添加有2%胎牛血清(Hyclone),16μg/ml肝素(ESI药学公司,Cher Hill,NJ),50μg/ml内皮细胞生长添加物(Collaborative Research Incorporated,Bedford MA),25mM Hepes缓冲液,2mM L-谷胺酰胺,100μg/ml青霉素和100μg/ml链霉素,在被有0.1%明胶剂的组织培养板上于37℃下培养。汇合后的细胞按1∶4进行传代。细胞要在前8代内使用。
与细胞因子和其它试剂孵育:汇合的HUVE细胞用磷酸盐缓冲液漂洗,然后换上新的培养基,在加细胞因子之前,加指定浓度的PDTC预处理30分钟。细胞因子和其它诱导物按每组实验所指定的浓度和时间直接加入培养基。人重组IL-1b由Upjohn公司(Kalamazoo,Michigan)慷慨馈赠。TNFα购自Bohringer Engelheim。细菌脂多糖(LPS),多聚肌苷酸∶胞苷酸(Poly I∶C),吡咯烷二硫代氨基甲酸盐(PDTC)购自Sigma Chemical公司(St.Louis,MO)。其它试剂均为试剂纯。
RNA提取:细胞总RNA的提取采用酸性硫氰酸胍-酚-氯仿混合物一步提取法。细胞用磷酸盐缓中液漂洗,然后用2ml异硫氰酸胍裂解。溶液用0.2ml醋酸钠(pH 4.0)进行酸化,用2ml酚和0.4ml氯仿∶异戊醇(24∶1)抽提。RNA在进行Northern杂交之前进行两次乙醇沉淀。
Northern印迹分析:取20μg细胞总RNA在含有1μg/ml溴化乙锭的1%琼脂糖甲醛凝胶上进行片段分离。将RNA从胶上转移到磷酸纤维素膜上,用Stratlinker紫外交联仪(Stratagene,La Jolla,CA)利用紫外光使RNA和膜共价偶联,于42℃杂交18小时,杂交缓冲液为5×SSC(1×=150mM NaCl,15mM柠檬酸钠),1%十二烷基磺酸钠,5×的Denhart液,50%甲酰胺,10%的硫酸葡聚糖(dextran sulfate)和100μg/ml的剪切过的变性鲑精DNA。每个杂交大约用1~2×106cpm/ml的标记探针(特定活性大于108cpm/μg DNA)。杂交结束后,用终浓度为0.2×SSC在55℃洗膜。在与其它探针进行又一次杂交前,要用沸水对硝酸纤维素膜去除核酸,加增感屏在-70℃放射自显影。
32P探针:用寡核苷酸随机引物法制备32P标记的DNA探针。ICAM-1探针是人cDNA用EcoRI切割的片段。ELAM-1探针是人cDNA用Hind III切割后的约1.85kb的片段。VCAM-1探针是人cDNA用HindIII和XhoI切割后的片段,包含132-1814核酸序列。
酶联免疫吸附分析(ELISA):实验前48-72小时将HUVE细胞种植在96孔组织培养板上。一抗溶于含5%FBS的M199中,直接加入每个孔,在37℃下孵育1小时。然后漂洗细胞,再与偶联了过氧化物酶的羊抗鼠IgG(BioRad)孵育1小时,这个二抗是按1∶500稀释在含5%FBS的M199中的。然后漂洗培养孔,加入100μl的10mg/ml3,3,5,5’-四甲基联苯胺(Sigma),并含有0.003%H2O2,对结合的抗体进行检测,加25μl 8N的硫酸终止反应。培养板在ELISA计数器(BIORAD)于450nm下计数,计数前先要计空白行,空白行是只用二抗染过色的一排孔,数据表示三次平行计数的平均值。
抗体:能识别血管细胞粘附分子的单克隆抗体(mAb)AB9是由John Harlan博士慷慨馈赠的。(华盛顿大学)。识别内皮细胞粘附分子的单抗E9A1F1是由Swerlic博士(Emory大学)慷慨馈赠的,识别胞间粘附分子1(ICAM-1)的单抗84H10是由杂交瘤分泌的,而杂交瘤细胞是我们实验室按常规方法培养,抗体用作组织培养的上清液。实施例9 PDTC阻断IL-1b介导的HUVEC VCAM-1,但不阻断
ICAM-1或ELAM-1 mRNA的累积
为了确定内皮细胞的氧化状态是否能改变基底的或诱导的细胞粘附分子基因的表达,用诱导性细胞因子IL-1b(10U/ml)作用于培养的人血管内皮细胞,作用分为能被烃硫基金属螯合的抗氧化剂吡咯烷二硫代氨基甲酸盐存在或不存在两种情况,作用长达24小时。如图10所示,单独使用IL-1b(2、4、6、8道)如预期那样迅速且瞬时诱导VCAM-1(A组),E-选择素(ELAM-1,B组)和ICAM-1(C组)mRNA的积累,所有这些都是在4小时达到峰值,但是在PDTC存在的情况下,IL-1b对VCAM-1mRNA积累的诱导被明显抑制,抑制大于90%(A组,3、5、7、9道)。与之不同,尽管IL-1b介导的ELAM-1诱导在2和24小时有轻微抑制(比较B组的2和3,8和9道),但PDTC在4和8小时(B组的5和7道)并不抑制。IL-1b介导的ICAM-1mRNA积累的诱导未受影响(B组3、5、7、8道)。实际上,由IL-1b诱导的ICAM-1 mRNA的累积还有中等强度增加(~30%)(比较B组的4道和5道)。每一泳道转移到硝酸纤维素膜上的RNA的量通过溴化乙锭染色并观察证实为相当。
做了剂量反应分析来确定PDTC对IL-1b诱导VCAM-1基因表达抑制是否有剂量依赖性。如图11所示,PDTC对IL-1b诱导VCAM-1基因表达的抑制呈现很陡的剂量反应曲线(图11,A组),计算EC50值约为10μM,而这些浓度下,PDTC并不能抑制IL-1b对ELAM-1表达的诱导(图11,B组)。而当浓度大于0.5mM时,PDTC增加IL-1b对ICAM-1 mRNA累积的诱导。(图12,比较C组的2和4~7道)。
这些数据表明,IL-1b对VCAM-1基因表达的诱导过程中,二硫代羧化物特别是二硫代氨基甲酸盐敏感性步骤是信号机制的一部分。数据似乎还表明这个二硫代氨基甲酸盐敏感性步骤对IL-1b诱导ELAM-1或ICAM-1基因表达不起重要作用。实施例10 PDTC阻断多种刺激诱导的HUVEC中VCAM-1 mRNA
的累积
为确定其它很清楚的VCAM-1基因表达激活剂也利用PDTC敏感性步骤,试验了三类不同的激活剂:另一类受体介导的诱导剂(TNFα),非受体介导的诱导者(脂多糖(LPS))和最近发现的新诱导者(双链RNA,Poly(I∶C))。所有三种情况下,作用4小时后,PDTC都明显抑制HUVEC受诱导后VCAM-1 mRNA积累(图12,A组)尽管TNFα介导的ELAM-1基因表达在某种程度上也受到抑制(图12,B组,1和2道),但LPS和Poly(I∶C)介导的ELAM-1 mRNA累积则未受影响(图12,B组,3-6道)。诱导ICAM-1 mRNA累积不受影响(图12,C组)。这些数据表明结构不同的诱导剂,通过不同途径发挥作用,但对诱导VCAM-1基因表达有一个特异性的共同的调节步骤。实施例11 PDTC阻断由多种刺激诱导的HUVE细胞表面VCAM-1
的表达
为确定内皮细胞表达VCAM-1的蛋白表达是否也象它的mRNA表达一样受PDTC抑制,采用ELISA分析法用单克隆抗体对培养的HUVE细胞表面诱导表达的VCAM-1和ICAM-1进行量化。如图13所示,在没有PDTC(-PDTC)的情况下,多种激活剂都能诱导细胞表达迅速且瞬时的VCAM-1的累积(顶部左面一组),在6小时达到峰值。在有PDTC(+PDTC,顶部右面一组)情况下,所有受测试剂所诱导的细胞表面VCAM-1的表达都受到明显抑制(80%~90%)与之不同,在相同的条件下,诱导的细胞表面ICAM-1的表达不受影响(底部左边和右边组)。
这些数据表明细胞表面VCAM-1的表达正如它的mRNA累积,也可被二硫代氨基甲酸盐选择性地抑制,并且多种类型的激活剂是通过相似的二硫代氨基甲酸盐敏感性机制来诱导VCAM-1基因表达。实施例12 抗氧化剂对TNF-α诱导VCAM-1表达的阻断效应比较
为了确定结构上相似或不相似的抗氧化剂是否也能抑制VCAM-1基因表达,效力如何,进行了以下实验,在四种不同的抗氧化剂,并且每一个都采用一系列不同的浓度,在它们存在或不存在的情况下分别用TNFα作用于HUVE细胞达6小时。如图1 4所示,二乙基二硫代氨基甲酸盐(DETC)和N-乙酰半胱氨酸(NAC)在浓度为5μM和30μM时抑制VCAM-1的表达。与之相比,PDTC是在5~50μM之间有效。铁金属螯合剂,去铁敏(desferroximine)在受测浓度下没有任何效果。实施例13 PDTC抑制由TNF诱导的VCAM-1/VLA-4介导的粘附
用例12所提出的方法对多种不同的抗氧化剂TNFα诱导HUVE细胞中VCAM-1的抑制能力进行了估测。图15是TNF-α激活HUVE细胞后VCAM-1在细胞表面的相对表达(O.D.595nm)比以下各药物的浓度:PDTC(N-吡咯烷二硫代氨基甲酸钠),DIDTC(N,N-二乙基-二硫代-N-甲酸钠),SarDTC(N-甲基-N-羧甲基-二硫代-N-甲酸钠),IDADTC(N,N-二(羧甲基)-二硫代-N-甲酸三钠),MGDTC(N-甲基-D-葡萄糖胺-二硫代-N-甲酸钠),MeOBGDTC(N-(4-甲氧苄基)-D-葡萄糖胺-二硫代-N-甲酸钠),DEDTC(N,N-二乙基-N-二硫代-N-甲酸钠),Di-PDTC(N,N-二异丙基-二硫代-N-甲酸钠)和NAC(N-乙酰半胱氨酸)。实施例13 PDTC抑制TNF对VCAM-1/VLA-4介导的粘附的诱导
为了确定PDTC对VCAM-1调节的抑制是否伴随着功能上的影响,在PDTC存在或不存在的情况下,用TNF-α(100U/ml)刺激或不刺激,持续作用6个小时同时检测Molt-4细胞与HUVEC的结合,前面已经表明Molt-4细胞通过依赖于VCAM-1的机制与激活的HUVRC结合。如图16所示,当培养基中有PDTC时,Molt-4与HUVEC结合的百分率下降。实施例14 PDTC抑制单核细胞与胆固醇喂养的兔子的胸部大动脉的结
合
为了确定硫醇抗氧化剂PDTC在阻断最初的单核细胞与实验动物模型中动脉粥样硬化成分相结合方面是否有效,进行了以下实验。一只成熟的新西兰白兔(3.5千克)静脉注射PDTC(20mg/kg,浓度为20mg/mlPBS),每天一次,进行5天。注射是通过耳缘静脉内插管,通过用肝素化的盐溶液冲洗,使耳缘静脉保持扩张。PDTC溶液可以每天配制新鲜的,或隔天配制(4℃避光保存),使用前过滤(0.45mm微孔滤膜)。第一次注射后,当把插管插好,药物与清醒状态下的兔子作用,没有明显不舒服或其它病变。第二天注射时,兔子按体重进含1%胆固醇的食物,并且在实验的后面部分持续这样的进食。第5天,给兔子施行安乐死,胸部大动脉切割并固定,经过适当的准备,在装备有LaB发射器的电子扫描显微镜的低倍(stage)下观察样品。用CRT屏幕上的二维图象和放大620倍的透明格子,对64个毗邻的区域进行了观测,覆盖面积约为1.3mm2,在每一区域内,记数并记录粘附的红细胞和白细胞。
从主动脉样品中得出的数据如下:每1.3mm2区域内约5个白细胞和25个红细胞。白细胞粘连水平近似于正常进食的对照动物(二个“阴性对照”实验中,主动脉(arch)和胸部样品中每一区域大约是7个)。“阳性对照”兔子连续4天进食1%的胆固醇,但没有注射抗氧化剂,粘附增加大约5倍,增加到(每1.3mm2 38个白细胞)。在每个主动脉样品中发现吸附有相当数量的几乎有细胞大小的碎片。还不清楚这种碎片是由于制备过程中的人为产物还是体内就有的。如果是体内原有的,它是否与PDTC的使用有关。这些研究表明PDTC的注入有效地阻断了最初的单核细胞与主动脉内皮细胞的粘连。实施例15 PDTC抑制BSA和13-HPODE的加合物
图18显示了PTDC对BSA和13-HPODE形成荧光加合物的影响,以荧光强度单位比PTDC的微摩尔浓度来估测。在含有PDTC的情况下,1μM的13-HPODE与200μg BSA共孵育6天。330~360nm激发,在430~460nm下测量荧光,反应的细节请参见Freebis,J.,Parthasarathy,S.,Steinberg,D,美国国家科学院院刊89,10588-10592,1992。典型的反应里,100nmol的LOOH(由脂氧化酶催化亚油酸氧化产生的)当100μg牛血清白蛋白孵育48~72小时,然后通过测定荧光光谱,360nm下激发390~500nm下发射,确定荧光产物的形成。
如图所示,PDTC降低了BSA和13-HPODE的荧光加合物的形成。
图19显示PTDC对BSA和ox-PUFA荧光加合物形成的影响,是波长(nm)和PDTC浓度之间的函数。当PTDC浓度增加时,荧光加合物的量降低。实施例16 PDTC对辣根过氧化酶氧化LDL的影响
图20显示了PDTC对辣根过氧化酶氧化LDL的影响,在不同浓度的PDTC作用一段时间(数分钟)后测量,LDL的氧化是通过测量LDL中脂肪酸成分的氧化来确定的,也即234nm下光密度的增加。当多不饱和脂肪酸被氧化后产生双键飘移(Shift),形成共轭双烯,它在234nm下有吸收峰,起始和扩展曲线(滞后期)之间的截取部分认为可以衡量LDL可被氧化的能力。滞后期越高,LDL抗氧化力越强。典型的,100μg人LDL与5μM H2O2共孵育,导致234nm下光吸收值增加。
发现经过一段时间的孵育之后,PDTC对HRP氧化的LDL的抑制是以浓度依赖的方式。实施例17 PDTC对细胞因子诱导ox-PUFA形成的影响
图21显示了PDTC对人主动脉内皮细胞中,细胞因子诱导ox-PUFA形成的影响。如图所示,TNF-α和IL-1B都能诱导亚油酸转变为氧化亚油酸,而PDTC很明显地抑制这个氧化。2.PUFA和氢化PUFA合成和代谢的修饰
通过修饰PUFAs氧化为ox-PUFAs的代谢途径也可以抑制VCAM-1的表达。例如,已知有一些酶能氧化不饱和物质,包括过氧化物酶,脂氧合酶,环氧合酶和细胞色素p450。体内抑制这些酶可以阻止PUFAs的氧化。PUFAs也可以被金属依赖性的非酶物质所氧化。IV.修饰氧化-还原敏感基因表达的方法
在另外的实施方案中,提供了抑制氧化-还原敏感基因或激活由氧化-还原敏感途径被抑制的基因的方法,包括使用有效剂量的防止氧化信号被氧化的物质,尤其是多不饱和脂肪酸的氧化。免疫反应传递过程中所包含的有代表性的氧化还原敏感性基因包括,但不限于,那些包含于启动免疫反应的表达细胞因子的基因(如,IL-1β),促进炎症细胞向受伤部位移动的趋化因子(如,MCP-1),生长因子(IL-6,凝血酶原受体),和粘附分子(如VCAM-1和E-选择素)。
基于上述发现,本领域的普通技术人员就可对更广泛范围的抗氧化剂进行筛选,以确定它们抑制氧化-还原敏感基因表达或激活被氧化-还原途径抑制的基因的能力。所有这些实施方案都将属于本发明的范畴。
据这种筛选结果,找到了含氧化-还原敏感基因5’-端调节序列的核酸分子,那个序列可以在体内调节或抑制基因表达。载体,包括质粒和真核病毒载体,可以用来在细胞内表达特定的重组的5’端侧翼区域基因构建体,这要依赖于熟练技术人员的优选和判断(参见,如Sambrook,等,16章)。另外,还发展了一些病毒和非病毒载体使核酸序列能导入体内。(参见Muligan,1993,Science,260,926-932;美国专利号4,980,286;美国专利号4,868,116;在此引入作为参考)。近来又发展了一种运载系统,将核酸包在阳离子脂质体中,通过静脉注射导入哺乳动物。这种体系已用来将DNA导入成年鼠的多种组织的细胞中,包括内皮细胞和骨髓(参见如,Zhu等,1993,Science 261,209~211;在此引入作为参考)。
氧化-还原敏感基因5’端侧翼序列能用来抑制这种基因的表达。例如,氧化-还原敏感基因5’端侧翼序列的全部或部分反义RNA能用来抑制该基因的体内表达。本领域已存在这样的载体(如逆转录病毒表达载体)能用来产生在某一细胞内表达的特定DNA序列的反义RNA(参见如,美国专利号4,868,116;美国专利号4,980,286)。因此,含有该基因全部或部分5’端侧翼序列的DNA可以插入合适的表达载体,这样,当传入细胞后,插入DNA的转录将产生反义RNA,与细胞中正常情况下存在的该基因转染产物mRNA互补。当然,选择该氧化-还原基因转录起始下游的5’端侧翼序列是很必要的,这能保证反义RNA含有与mRNA互补的序列。反义RNA也可以在体外产生再插入细胞,可以在自动合成仪上合成寡核苷酸(如,8700型自动合成仪,Milligen-Biosearch公司,Bwrlington,MA或ABI 380B型)。另外,发现反义脱氧寡核苷酸对抑制基因转录和病毒复制有效(参见,如Zamecnik等,1978,美国国家科学院院刊75,280-284;Zamecnik等,1986,美国国家科学院院刊83,43-4146;Wickstrom等,1988,美国国家科学院院刊85,1028-1032;Crook,1993 FASEB J.7,533-539。另外最近的工作表明如果反义RNA寡核苷酸中含有修饰过的核苷酸,反义寡核苷酸对基因表达的抑制效应就可能增加(参见如,offensperger等,1993,EMBO J.12,1257-1262(反义寡聚脱氧核苷酸的硫代磷酸盐体内抑制鸭B型肝炎病毒复制与基因表达);Rosenberg等,PCT WO 93/01286(寡核苷酸的硫代磺酸盐的合成);Agrawal等,1988,美国国家科学院院刊85,7079-7083(合成反义寡核苷酸的氨基磷酸酯和硫代磷酸酯抑制人免疫缺陷病毒1的复制);Sarin等,1989,美国国家科学院院刊85,7448-7794(反义甲基磷酸酯寡核苷酸);Shaw等,1991,核酸研究19,747-750(含有3’端氨基磷酸酯修饰并抗核酸外切酶的寡核苷酸的合成);在此引入作为参考)。
氧化-还原敏感基因的5’端侧翼序列也能用于三螺旋(三股螺旋)基因治疗。与DNA双链的一条上的基因启动子序列互补的寡核苷酸可以结合启动子与调节序列,形成局部三股核酸螺旋,阻抑基因的转录(参见,如,1989 Maher等,Science 245,725-730;Crson等,1991,美国国家科学院院刊88,8227-8231;Cooney等.,1988Science.241,456-459;Yong等,1991,美国国家科学院院刊88,10023-10026;Dwval-Valentin等.,1992,美国国家科学院院刊89,504-508;1992 Blume等.,核酸研究20,1777-1784;1992Grigoriev等,生物化学杂志267,3389-3395。
近来报道的理论计算和经验报道为寡核苷酸的设计提供了指导,用于寡核苷酸引导的三股螺旋的形成来抑制基因表达。例如,一般来说寡核苷酸长度应大于14个核苷酸以确保靶序列特异性(参见,如Maher etal.,(1989);Grigoriev等,(1992))。许多细胞也能很容易地吸收长度小于50的寡核苷酸。(参见如,Orson等,(1991);Holt等.,1988,分子细胞生物学8,963-973;Wickstrom等,1988,美国国家科学院院刊85,1028-1032)。为了降低对胞内降解的敏感性,如3’核酸外切酶,可以在寡核苷酸3’端的羟基上引入自由氨基,而序列结合特异性并不丢失(Drson等,1991)。另外,如果寡核苷酸中的任意一个胞苷酸都被甲基化,而且如果嵌合剂如吖啶衍生物共价地偶联到5’端磷酸如,通过一个1,5-亚戊基桥上,就会形成更稳定的三股螺旋,也不会使序列特异性丢失(Maher等,(1989);GrigorieV等,(1992)。
产生或合成寡核苷酸的方法是本领域熟知的,可以通过规范的酶消化后核苷酸片段分离(参见如,Sambrook等.,第5、6章),也可以是单纯合成的方法,如通过氰乙基磷酰亚胺方法,用Milligen或Beckman公司的System 1Plus DNA合成4(参见, Ikuta等,Ann.Rev.Biochem.1 984,53,323-356(磷酸三酯和亚磷酸-三酯的方法);Narang等.,Methods Enzymol.,65,610-620(1980)(磷酸三酯法))。因此,这里描述的氧化-还原基因的5’侧翼区的序列能用来设计和构建包含有一段特定DNA序列的寡核苷酸,这段序列中又包含有很本质的至少15个连续的核苷酸,可采用也可不采用碱基修饰或嵌合剂衍生物作用。然后这段寡核苷酸就特异性地在氧化-还原敏感基因的5’侧翼区内形成三螺旋,阻止该基因的表达。
在某些情况下,在表达体系中插入增强子或多拷贝的调节序列有利于操纵表达的方法与试剂进行搜寻。V.模型和筛选
也给出了VCAM-1介导的紊乱或氧化-还原敏感基因的筛选方法,包括疾病替代标记的量化。在一个实施方案中,估测某病人如组织或血液等的氧化多不饱和脂肪酸水平或其它合适标记的水平可以作为衡量病人“氧化环境”及病人对VCAM-1或氧化-还原敏感基因介导的疾病敏感性的方式。
另一实施方案中,循环的和细胞表面的VCAM-1分子或其它合适的标记物的水平以及使用某种合适的抗氧化剂后对那个水平的影响都进行了量化。
在其它测试中,就病人血管内皮细胞对多不饱和脂肪酸或其氧化产物的感受性进行了估量,比如这可以通过用PUFA或ox-PUFA刺激病人,然后与正常群体细胞表面或循环中VCAM-1浓度进行比较,就可以得出结果。
在另一实施方案中,通过对实验动物施用过量PUFA或氧化PUFA诱导疾病的途径,建立了动脉粥样硬化或其它由VCAM-1介导的心脏或发炎病症的在体模型。
本发明的又一实施方案中,依据化合物抑制多不饱和脂肪酸的氧化或PUFA或氧化PUFA与靶蛋白相互作用的能力,估测此化合物对疾病的治疗能力。
这可以由以下方法实现,如刺激主体,人或动物如小鼠,使其达到较高的PUFA或氧化PUFA水平,然后依据受试化合物降低循环或细胞表面VCAM-1浓度的能力来确定它的疗效。另外,也可以采取体外筛选的办法,即根据受试化合物抑制PUFA被氧化的能力,或在氧化物质如金属比如铜或酶如过氧化物酶,脂氧合酶,环氧合酶或细胞色素P450等存在的情况下,此化合物抑制PUFA或氧化的PUFA与靶蛋白作用的能力来筛选。
在另一种实施方案中,先用TNF-α或其它VCAM-1诱导物对血管内皮细胞作用合适的时间,然后通过任何合适的方式终止,如超声或冻融。分离胞浆和膜部分,将放射性标记的PUFA加入定量的部分收集物中。在有或没有受试物的情况下,分别分析液体样品将PUFA转化为氧化PUFA的能力。也可以用全细胞来代替破碎细胞体系。III.药用组合物
人、马、狗、牛和其它动物,特别是哺乳动物,患有心血管病或其它由VCAM-1或氧化还原敏感基因介导的炎症后,可以对病者施有效量的某化合物进行治疗,该化合物能移去氧化多不饱和脂肪酸,降低其浓度或阻碍其形成,氧化多不饱和脂肪酸包括但并不限于氧化亚油酸(C18Δ9,12),亚麻酸(C18Δ6,9,12),花生四烯酸(C20Δ5,8,11,14)和二十碳三烯酸(C20Δ8,11,14);或也可施用其它氧化信号;或其它活性化合物或药用的衍生物或其盐,这种衍生物或其盐在某药用载体或稀释剂中,活性物质可以通过任何适当的途径施用,如口服,肠胃外施用,静脉注射,皮内注射,皮下注射,或局部敷用。
这里所说的药用盐或复合物指的是保留了以上确认的化合物期望的生物活性,并且只有很小的非期望的毒性效应的盐或复合物。这些盐的非限制性例子如下:(a)与无机酸形成的酸加成盐(如氢氯酸、氢溴酸、硫酸、磷酸、硝酸等),与有机酸形成的盐如乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、pamoic酸、藻酸、聚谷氨酸、萘磺酸、萘基二磺酸、聚半乳糖醛酸(b)与多价金属阳离子形成的碱加成盐,如锌、钙、铋、钡、镁、铝、铜、钴、镍、镉、钠、钾等,或与有机阳离子形成盐,这些阳离子来自N,N-二苄基-1,2-乙二胺,D-葡萄糖胺、氨、四乙胺或1,2-乙二胺;或(c)(a)和(b)结合;如锌与鞣酸盐形成的盐,诸如此类。
这些活性化合物或其混合物可以通过任意适当的途径服用,包括但并不限于口服或静脉给药。总的来说,对上面提到的任一种病情,剂量范围大致是从每千克体重0.5-500mg,服药频率从两天一次到一天几次,优选的每日剂量约为每个病人每天1~3000mg,更优选的是5~500mg,再优选的是25~500mg。
活性成分使用后,应使得这些活性化合物在血浆的最大浓度约达0.1~100μM,优选浓度是1~10μM。这可以按下述方法实现,如静脉注射活性成分的溶液或制剂,一般选用盐溶液或水介质基质,或者将活性成分制成药丸来服用。
这些化合物也可以用灌注气球导管(perfusion balloon cather)在其之后或代替的冠状动脉或其它动脉血管造形术(arterialangioplasty)直接施于血管壁。例如,含有大约1~500μM的化合物或其混合物的2~56ml的生理上可接受溶液,要在1~5个大气压下施用。此后,经过再狭窄最大危险期中6个月的过程后,活性化合物就可以通过其它合适的途径和剂量制度来施用。
用活性化合物进行相对短期治疗常导致冠状动脉病患处的“回缩”,这是造形术和手术都达不到的。短期治疗的非限制性的例子如2~6个月,每千克体重0.5~500mg的剂量,隔天一次或一天三次。
长期治疗用来防止高危病人严重患处的发展。长期治疗可持续数年,剂量每千克体重0.5~500mg,隔天一次或一天三次服用。
活性物质也可以在冠状动脉血管造形术之前和之后一段时间立即服用,作为降低或消除不正常增殖和炎症反应的方式,而这些反应目前常导致临床上严重的血管再狭窄。
这些活性化合物也可与用来治疗心血管疾病的其它治疗结合使用,如降脂剂如普罗布考和尼古丁酸;血小板凝集抑制剂如阿司匹林;钙通道阻断剂如维拉帕米(varapamil),地尔硫(diltiazem)和硝苯地平(nifedipine);血管紧张素转化酶(ACE)抑制剂如卡托普利(catopril)和依那普利(enalopril);β-阻断剂如propanalol,turbutalol,和拉贝洛尔(labetalol),该类化合物也可以与非甾醇类抗炎症物质结合使用,如布洛芬(ibuprofen),吲哚美辛(indomethacin),非诺洛芬(fenoprofen),甲芬那酸(mefenamic acid),氟芬那酸(flufenamic acid),舒林酸(sulindac)。该化合物也可与肾上腺皮质类固醇结合使用。
药物组合物中活性化合物的浓度要依药物的吸收,分布,失活和分泌速率来定,还有其它一些本领域技术人员熟知的因素。还有一点值得注意,剂量依所治疗病情的严重性而有变化。另外还要明白,针对任意一个治疗对象,特定剂量都应该过一段时间后进行调整,根据病人的需要和施用及观察药物使用的医生的专业判断,而且这里所提出的浓度范围也仅仅是例子,并不是要限制权利要求所要求的范围或实践。活性组分可一次使用,或可分成一些小剂量按不同的间隔使用。
口服组合物一般要包括惰性稀释剂或可食载体。它们可以包于明胶胶囊里或压缩成药片。针对口服使用的目的,活性化合物可与赋形剂整合,以药片,药锭或胶囊的形式使用。药学上匹配的结合剂和/或佐剂也可以包含于该组合物中。
药片、药丸、胶囊、药锭等可包含以下任意组分或本质相似的化合物:结合剂如结晶纤维素,黄蓍树胶或明胶;赋形剂如淀粉或乳糖,崩解剂如藻酸,Primogel或玉米淀粉;润滑剂如硬脂酸镁或Sterotes;助流剂如胶体二氧化硅;甜味剂如蔗糖或糖精;调味剂如薄荷、水杨酸甲酯,或桔精,当剂量单位的形式是胶囊时,除上述类型的物质外还可以含有液体载体如脂肪类油性物质。另外,剂量单位的形式可以含各种其它物质,用以修饰剂量单位的外形,如糖衣,虫胶,或其它肠内吸收剂。
活性化合物或其药用盐或衍生物可以作为酏剂,悬液,糖浆,糯米纸囊剂、咀嚼胶等的组分来施用。糖浆除了活性物外,还含有蔗糖作为甜味剂,还含有某些防腐剂,染料和着色剂和香味剂。
活性化合物或药学上可接受的衍生物或盐也可以与其它活性物质一起使用,那种物质要不影响所期望的效应或能补充期望的效应,如:抗生素,抗真菌剂,抗炎症剂或抗病毒化合物。
用于胃肠道,皮内,皮下和局部敷用的溶液或悬液包括下述成分:灭菌稀释剂如水,能用于注射,盐溶液,固化的油,聚乙二醇,甘油,丙二醇或其它合成的溶剂;抗菌剂如苄醇或对羟基苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸钠;螯合剂如乙二胺四乙酸;缓冲液如乙酸,柠檬酸或磷酸,和调节渗透压的试剂如NaCl或右旋糖。与之同是进行的准备就是装药的安瓿,一次性注射器或用玻璃或塑料制成的多次剂量的小瓶。
已知的局部敷用的合适渠道或载体包括洗剂(lotions),悬液,药膏,霜,胶,酊剂,喷湿剂,粉末,糊状,缓释透皮斑,治疗哮喘的气雾剂,用于直肠,阴道,鼻或口腔粘膜的栓剂。
稠合剂,润滑剂和稳定剂可用于制备局部敷用的组合物,稠合剂的例子包括凡士林,蜂蜡,黄原增胶或聚乙二醇,润湿剂如山梨醇,润滑剂矿物质油,羊毛脂及其衍生物或鲨烯。一些溶液和药膏是市场上可购得的。
天然或人工的加味剂或甜味剂可以增加用于粘膜表面使产生局部效应的局部制剂的味道,当用于口腔粘膜表面时制备中可以加惰性染料和着色剂。
活性化合物可与载体一起制备,载体可以防止活性物迅速释放,如有控制的释放制剂,包括植入和微胶囊运送体系。生物可降解,可匹配的聚合物都可以用,如亚乙基乙酸乙烯酯,聚酸酐,聚羟基乙酸(glycolicacid),胶原蛋白,聚原酸酯,和聚乳酸。这些制剂的制备方法许多是申请了专利的或本领域技术人员所熟知的。
如果静脉注射,优选的载体是生理盐水或磷酸缓冲盐水(PBS)。
活性化合物也可以通过透皮斑施用。制备这种斑片的方法是本领域技术人员所知的。如参见Brown,L.,和Langer,R.,药物透皮肤运送,Annul Review of Medicion,39:221-229(1988),在此引入作为参考。
在另一实施方案中,活性物质与载体一起制备,防止化合物从体内迅速消失,如受控的释放制剂,包括植入或微胶囊运送系统。可使用生物可降解,可匹配的聚合物,如亚乙基乙酸乙烯酯,聚酸酐,聚羟基乙酸,胶原蛋白,聚原酸酯,和聚乳酸。制备这些制剂的方法是本领域技术人员熟知的。这些物质也可以从Alzo公司和Novo Pharmaceticals公司购得。
脂质体悬液也可以作为药用载体,这些制备可以按本领域技术人员所知的方法进行。如美国专利号4,522,811所描述的(在此引入它的全部作为参考)。例如,脂质体制剂的制备可以通过将适当的脂(如硬脂酰磷乙醇胺,硬脂酰磷酰胆碱,花生四烯酰磷酰胆碱,和胆固醇)溶于无机溶剂,然后将溶剂蒸发,在容器表面就留下一层干的脂质薄膜。然后活性化合物或它的单磷酸酯,二磷酸酯,和/或三磷酸酯衍生物的液体溶液加到容器中,然后手动旋转容器,使脂类物质从容器壁上释放,也使脂聚集体分散,这样就形成脂质体悬液。
从前面本发明所描述的细节,对本领域那些技术人员来说本发明的修饰及各种变化是显而易见的。这种修饰和变化是属于所附的权利要求的范畴的。
Claims (49)
1.一种抑制VCAM-1表达的方法,它包括用有效剂量的物质阻止或最大限度减少多不饱和脂肪酸的氧化。
2.一种抑制氧化-还原敏感基因表达的方法,它包括用有效量的物质阻止或最大限度减少多不饱和脂肪酸的氧化。
3.一种激活由多不饱和脂肪酸的氧化而受抑制的基因的方法,它包括用有效量的物质阻止或最大限度减少多不饱和脂肪酸的氧化。
4.一种抑制VCAM-1表达的方法,它包括用有效剂量的物质阻止多不饱和脂肪酸和介导VCAM-1表达的蛋白之间的相互作用。
5.权利要求1-4的方法,其中多不饱和脂肪酸选自氧化亚油酸(C18Δ9,12),亚麻酸(C18Δ6,912),花生四烯酸(C20Δ5,8,11,14)和二十碳三烯酸(C20Δ8,11,14)。
6.权利要求2或3的方法,其中氧化-还原敏感基因选自那些在起始免疫反应中表达细胞因子(如IL-1β),促进发炎细胞向损伤点移动的趋化因子(如,MCP-1),生长因子(如IL-6和凝血酶受体),和粘附分子(如VCAM-1和E-选择素)的基因。
7.权利要求1~4中的方法,其中的物质是吡咯烷二硫代氨基甲酸盐或其药用盐。
8.一种预见或诊断体内由VCAM-1介导的疾病的方法,它包括对组织或血液中氧化多不饱和脂肪酸水平的定量化。
9.一种预见或评估体内由氧化-还原敏感基因介导的疾病的方法,它包括对组织或血液中氧化多不饱和脂肪酸水平的量化。
11.一种预见或评估体内由VCAM-1介导的疾病的方法,它包括对组织或血液中氧化多不饱和脂肪酸水平替代标志的量化。
12.一种预见或评估体内由氧化-还原敏感基因介导的疾病的方法,它包括对组织或血液中氧化多不饱和脂肪酸水平替代标记的量化。
13.权利要求11方法,其中的替代标志是循环的或细胞表面的VCAM-1。
14.估测主体血管内皮细胞对多不饱和脂肪酸及其氧化产物的感受性的方法,它包括用PUFA或氧化PUFA刺激主体,并与正常群体细胞表面或循环中的VCAM-1或其它替代标志的浓度进行比较。
15.一种筛选能治疗VCAM-1介导的疾病的化合物方法,它包括估测化合物对多不饱和脂肪酸氧化的抑制能力。
16.一种筛选能治疗由VCAM-1介导的疾病的化合物方法,它包括估测化合物对多不饱和脂肪酸或其氧化产物与蛋白靶相互作用的抑制能力。
17.一种治疗人心血管疾病的方法,包括使用有效量的通式为A-SC(S)-B的二硫代氨基甲酸盐,
其中A选自氢原子,药用阳离子和生理上可切割的离去基团;
并且其中B选自烷基、链烯基、炔基、烷芳基、芳烷基、卤代烷基、卤代链烯基、卤代炔基、芳基、烷芳基、氢原子、C1-6烷氧基-C1-10烷基、C1-6烷基硫代-C1-10烷基、NR2R3、-(CHOH)nCH2OH,其中n是0、1、2、3、4、5或6,-(CH2)nCO2R1,包括烷基乙酰基、烷基丙酰基、和烷基丁酰基和羟基(C1-6)烷基。
18.权利要求17的方法,其中A是氢原子或选自钠、钾、钙、镁、铝、锌、铋、钡、铜、钴、镍或镉的或药用阳离子。
19.权利要求17的方法,其中A是成盐的有机酸。
20.权利要求19的方法,其中A选自胆碱、乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、Pamoic酸、藻酸、聚谷氨酸、萘磺酸、萘基二磺酸和聚半乳糖醛酸。
21.权利要求17的方法,其中A是由氨或其它含氮碱形成的阳离子。
22.权利要求2 1的方法,其中A是含氮杂环或通式NR4R5R6R7的一部分,其中R4、R5、R6和R7分别是氢原子、C1-6烷基、羟基(C1-6)烷基、芳香基、N,N-二苄基亚乙基二胺、D-葡萄糖胺、四乙胺、或1,2-乙二胺。
23.权利要求17的方法,其中A是生理上可切割的离去基团。
24.权利要求17的方法,其中A是酰基。
25.权利要求17的方法,其中B是NR2R3,其中R2和R3选自烷基,-(CHOH)n(CH2)nOH,其中n是0,1,2,3,4,5或6;-(CH2)nCO2R1,-(CH2)nCO2R4;羟基C1-6烷基;链烯基、烷基(CO2H),链烯基(CO2H),炔基(CO2H)或芳香基,或R2和R3可一起搭桥为通式-(CH2)m-,其中m是3,4,5或6,而R4选自芳香基,烷芳基,芳烷基,包括乙酰基、丙酰基或丁酰基。
26.权利要求17的方法,其中B是杂环或烷基杂环基团。
27.权利要求26的方法,其中杂环是部分或全部被氢化的。
28.权利要求17的方法,其中B是有药用活性化合物或药物的残基,它可直接连于A-SC(S)-或通过双键连接部分与之连接。
29.权利要求17的方法,其中B选自普罗布考(probucol),尼古丁酸,阿司匹林,苄丙酮香豆素钠,维拉帕米(varapamil),地尔硫(diltiazem),硝苯地平(nifedipine),卡托普利(captopril),依那普利(enalopril),propanalol,turbutalol,拉贝洛尔(labetalol),布洛芬(ibuprofen),吲哚美辛(indomethacin),非诺洛芬(fenoprofen),甲芬那酸(mefenamic acid),氟芬那酸(flufenamicacid),舒林酸(sulindac)及皮质甾类。
30.权利要求17的方法,其中二硫代氨基甲酸盐是结构为AO2C-R9-NR10-C(S)SA的氨基酸衍生物,其中R9是B或氨基酸的内部残基,R10是氢原子或低级烷基。
31.权利要求17的方法,其中B是一个或直接或通过任何合适的连接部分与一个或多个二硫代氨基甲酸盐基团连接的聚合物。
32.权利要求17的方法,其中聚合物是生物可降解的。
33.权利要求32的方法中,聚合物选自肽、蛋白、核蛋白、脂蛋白、糖蛋白、合成或天然多肽和聚氨基酸、聚原酸酯、聚(α-羟基酸)、聚酸酐、多糖、聚己内酯。
34.权利要求1的方法中B-C(S)S-是吡咯烷-N-二硫代羧化物。
35.权利要求17的方法,其中心血管病是动脉粥样硬化。
36.权利要求17的方法,其中心血管病是血管成形术后再狭窄。
37.权利要求17的方法,其中心血管病是冠状动脉病。
38.权利要求17的方法,其中心血管病是绞痛。
39.权利要求17的方法,其中心血管病是小血管病。
40.权利要求17的方法,其中二硫代氨基甲酸盐使用剂量是每公斤体重0.5~500mg。
41.权利要求17的方法中,二硫代氨基甲酸盐是通过灌注气球(Perfusion balloon)导管来施用的。
42.权利要求17的方法,其中二硫代氨基甲酸盐可以和选自降脂剂、血小板凝集抑制因子、抗凝血酶试剂、钙通道阻断剂、血管紧张素转化酶(ACE)抑制因子、β-阻断剂、非甾醇类抗炎剂和皮质甾醇的药剂结合使用。
43.一种抑制人细胞中VCAM-1表达的方法,包括用有效剂量的权利要求17中所描述的二硫代氨基甲酸盐。
44.一种治疗VCAM-1介导的皮肤炎症的方法,包括用有效剂量的权利要求17中所描述的二硫代氨基甲酸盐。
45.一种治疗VCAM-1介导的内皮疾病的方法,包括用有效剂量的权利要求17中所描述的二硫代氨基甲酸盐。
46.权利要求45的方法,其中的疾病包括:哮喘、牛皮癣、湿疹性皮炎、卡波济肉瘤、多发性硬化和平滑肌细胞增殖紊乱。
47.一种治疗由单核细胞介导的炎症的方法,它包括权利要求17中所描述的有效量的二硫代氨基甲酸盐。
48.权利要求17-34任一项中所说的二硫代氨基甲酸盐。
49.一种包含权利要求17-34中任一项所说的对治疗心血管疾病有效剂量的化合物的药用组合物。
50.一种包含权利要求17-34的任一项所说的对治疗VCAM-1介导疾病有效量的化合物的药用组合物。
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US24085894A | 1994-05-10 | 1994-05-10 | |
US08/240,858 | 1994-05-10 | ||
US08/317,399 | 1994-10-04 | ||
US08/317,399 US5807884A (en) | 1992-10-30 | 1994-10-04 | Treatment for atherosclerosis and other cardiovascular and inflammatory diseases |
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CN1152869A true CN1152869A (zh) | 1997-06-25 |
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CN95194077A Pending CN1152869A (zh) | 1994-05-10 | 1995-05-10 | 动脉粥样硬化和其它心血管疾病及炎症的治疗方法 |
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US (6) | US5807884A (zh) |
EP (1) | EP0759752A4 (zh) |
JP (1) | JP3120091B2 (zh) |
KR (1) | KR100394157B1 (zh) |
CN (1) | CN1152869A (zh) |
BG (1) | BG101030A (zh) |
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CA (1) | CA2189336A1 (zh) |
CZ (1) | CZ330896A3 (zh) |
GE (1) | GEP20012409B (zh) |
HU (1) | HUT76728A (zh) |
MX (1) | MX9605450A (zh) |
NO (1) | NO964742L (zh) |
NZ (1) | NZ287214A (zh) |
PL (2) | PL180874B1 (zh) |
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WO1995030415A1 (en) | 1995-11-16 |
US5773209A (en) | 1998-06-30 |
EP0759752A4 (en) | 2001-08-08 |
NO964742D0 (no) | 1996-11-08 |
CA2189336A1 (en) | 1995-11-16 |
US5811449A (en) | 1998-09-22 |
JP3120091B2 (ja) | 2000-12-25 |
US5750351A (en) | 1998-05-12 |
PL180874B1 (pl) | 2001-04-30 |
HUT76728A (en) | 1997-11-28 |
MX9605450A (es) | 1997-12-31 |
US5807884A (en) | 1998-09-15 |
GEP20012409B (en) | 2001-04-25 |
PL184466B1 (pl) | 2002-11-29 |
BR9507716A (pt) | 1997-09-23 |
SK136496A3 (en) | 1999-01-11 |
BG101030A (en) | 1997-09-30 |
KR100394157B1 (ko) | 2004-02-11 |
US5773231A (en) | 1998-06-30 |
US5846959A (en) | 1998-12-08 |
NO964742L (no) | 1996-11-08 |
EP0759752A1 (en) | 1997-03-05 |
CZ330896A3 (cs) | 1998-07-15 |
HU9603041D0 (en) | 1997-01-28 |
JPH10500111A (ja) | 1998-01-06 |
NZ287214A (en) | 2001-05-25 |
PL317193A1 (en) | 1997-03-17 |
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